Hydrogel-forming material, premix, and hydrogel formation method

ABSTRACT

A hydrogel-forming material, a premix, and a method for forming a hydrogel through a simple process at room temperature. The material including: a disperse phase (A) including a lipid peptide-based gelator including at least one of a compound of Formula (1) or pharmaceutically usable salt thereof, water, and a fatty acid salt; and a phase (B) that includes a water-soluble acidic polymer: 
     
       
         
         
             
             
         
       
     
     (where R1 is a C9-23 aliphatic group, R2 is a hydrogen atom or a C1-4 alkyl group that optionally has a C1-2 branched chain, R3 is a —(CH2)n-X group, n is a number of 1 to 4, X is an amino group, a guanidino group, a —CONH2 group, a 5-membered ring optionally containing 1 to 3 nitrogen atom(s), a 6-membered ring optionally containing 1 to 3 nitrogen atom(s), or a condensed heterocycle that contains a 5-membered ring and a 6-membered ring optionally containing 1 to 3 nitrogen atom(s)).

TECHNICAL FIELD

The present invention relates to a hydrogel-forming material, a premixincluding a low-molecular lipid peptide-based gelator useful as agelator, and a method for forming a hydrogel.

BACKGROUND ART

A hydrogel contains water as its medium and is therefore useful as ahighly biocompatible gel. This gives a hydrogel a wide range ofapplications, for example, in the fields including daily necessitiessuch as disposable diapers, cosmetics, and fragrances.

A conventional hydrogel is a polymer gel that is obtained from polymerchains crosslinked to form a three-dimensional network structure whichis then bonded to a medium such as water through non-covalent bonds tocause swelling. The physical properties and the applications of such apolymer gel have been researched in large number on natural polymer gelscontaining a polysaccharide such as agarose and a protein and onsynthetic polymer gels such as a acrylamide gel obtained by formingcrosslinks between polymer chains through chemical covalent bonds.

Besides these gels that contain polymer compounds, a hydrogel that isobtained by self-assembling of an organic compound having relatively lowmolecular weight has been developed and extensively studied in recentyears.

Most of the low-molecular gelators that have already been developed areamphiphilic compounds having a combination of a hydrophobic moiety thatis a long-chain alkyl group and a hydrophilic moiety, and examples ofthese gelators include one having an amino acid [Non-patent Document 1],one having a peptide [Patent Documents 1 and 2], one having a saccharide[Non-patent Documents 2 and 3], and one having a polyol [Non-patentDocument 4], as the hydrophilic moiety. In addition, a low-moleculargelator that utilizes the characteristics of a peptide consisting ofvaline to readily form a β-sheet structure has been developed[Non-patent Document 5].

Using the low-molecular hydrogelators described above, a hydrogel can beformed by stirring the hydrogelators and water as a medium with heatingat the temperature of about 100° C. so that the hydrogelators aredissolved and dispersed in water, and by leaving the resulting solutionstill standing at room temperature.

PRIOR ART DOCUMENTS Patent Documents

Patent Document 1: WO 2009/005151 pamphlet

Patent Document 2: WO 2009/005152 pamphlet

Non-Patent Documents

Non-patent Document 1: Suzuki, Masahiro. Yumoto, Mariko. Mutsumi,Shirai. Hirofusa, Hanabusa, Kenji. Chemistry Letters, 33(11), 1496-1497.

Non-patent Document 2: Jong Hwa Jung, Georeg John, Mitsutosish Mausda,Kaname Yoshida, Seiji Shinnkai, and Toshimi Shimizu Langumir 2001, 17,7229-7232.

Non-patent Document 3: I. Hamachi, S. Kiyonaka, S. Shinkai, TetrahedronLett., 2001, 42, 6141.

I. Hamachi, S. Kiyonaka, S. Shinaki, Chem. Commun., 2000, 1281.

Non-patent Document 4: Masahiro Suzuki, Sanae Owa, Hirofusa Shirai andKenji Hanabusa, Tetrahedron 2007 63 7302-7308.

Non-patent Document 5: Yoko Matsuzawa, Katsuyuki Ueki, Masaru Yoshida,Nobuyuki Tamaoki, Tohru Nakamura, Hideki Sakai, and Masahiko Abe, Adv.Funct. Mater. 2007, 17, 1507-1514.

SUMMARY OF THE INVENTION Problem to be Solved by the Invention

Conventional methods disclosed at least by the present applicant forforming a gel with such low-molecular gelators are processes of heatingand stirring so that the gelator is dissolved and dispersed in a mediumand then leaving the system still standing at near room temperature forcooling, in other words, a single system process for gel formation.

However, with this single-system process, various problems leave arisenas scaling up the hydrogel production.

One of the problems is that dissolving and dispersing the gelator inwater serving as a medium need to be performed under conditions in whichthe temperature is as high as 100° C., which tends to cause denaturationof added ingredients. Therefore, additives that are easily affected byheat cannot be added, which in turn limits the applications of theresulting gel. Another problem is that conditions with high temperaturesrequire more time for cooling to reach room temperature, which isdisadvantageous in terms of productivity. Yet another problem is thathigh temperatures during production bring up safety issues and alsoincrease production cost.

An additional problem is that, in the process of leaving the system inwhich a hydrogel is formed still standing at near room temperature afterthe gelator is dissolved and dispersed in water, the system is notuniformly cooled, causing the quality of the resulting hydrogel to beinconsistent. This is disadvantageous in terms of quality control.

As described above, the production conditions in the conventionalsingle-system gel formation method are disadvantageous for hydrogelproduction on an industrial scale in terms of, for example, operability,cost, and quality control and performance of the resulting gel. In otherwords, further improvement has been demanded in large-scale hydrogelproduction in terms of productivity, production safety, and consistencyin quality.

The present invention is devised based on the above circumstances, andan object of the present invention is to provide a hydrogel-formingmaterial, a premix, and a method for forming a hydrogel, which can forma hydrogel through a relatively simple process and under relativelygentle conditions in terms of temperature (at room temperature).

Means for Solving the Problem

The inventors of the present invention have conducted intensive researchto achieve the object and, as a result, have found that mixing adisperse phase including a gelator and a fatty acid salt with an acidicsolution (disperse phase) results in an increase in viscosity to allow ahydrogel to be formed at room temperature and that the disperse phaseincluding a gelator and a fatty acid salt can be kept in a liquid stateat room temperature so as to be effectively used as a premix forhydrogel preparation.

More specifically, the inventors of the present invention have foundthat a gel can be prepared by stirring, at room temperature, abinary-system hydrogel-forming material that includes a disperse phaseincluding a lipid peptide-based gelator consisting of a low-molecularlipid peptide or a pharmaceutically usable salt thereof, water, and afatty acid salt, and a disperse phase including a water-soluble acidicpolymer. Thus, the present invention has been completed.

The inventors of the present invention have also found that the lipidpeptide-based gelator to which a fatty acid salt is added exhibitsexcellent dispersibility and solubility in water under gentlerconditions than conventional conditions in terms of temperature, andsuch gelator can be suitably used as a gel premix material that can bestored at room temperature by being left to cool with stirring afterheating.

Thus, the present invention relates to, as a first aspect, ahydrogel-forming material comprising: a disperse phase (A) including alipid peptide-based gelator consisting of at least one of a compound ofFormula (1) or a pharmaceutically usable salt thereof, water, and afatty acid salt; and a disperse phase (B) that includes a water-solubleacidic polymer increasing viscosity by neutralization:

(where R¹ is a C₉₋₂₃ aliphatic group, R² is a hydrogen atom or a C₁₋₄alkyl group that optionally has a C₁₋₂ branched chain, R³ is a—(CH₂)_(n)—X group, n is a number of 1 to 4, X is an amino group, aguanidine group, a —CONH₂ group, a 5-membered ring optionally containing1 to 3 nitrogen atom(s), a 6-membered ring optionally containing 1 to 3nitrogen atom(s), or a condensed heterocycle that contains a 5-memberedring and a 6-membered ring optionally containing 1 to 3 nitrogenatom(s)).

As a second aspect, in the hydrogel-forming material according to thefirst aspect, the disperse phase (A) includes at least one fatty acidsalt selected from the group consisting of butyrates, valerates,caproates, enanthates, caprylates, pelargonates, caprates, laurates,myristates, pentadecylates, palmitates, palmitoleates, margarates,stearates, oleates, vaccenates, linoleates, (9,12,15)-linolenates,(6,9,12)-linolenates, eleostearates, tuberculostearates, arachidates,arachidonates, behenates, lignocerates, nervonates, cerotates,montanates, and melissates.

As a third aspect, in the hydrogel-forming material according to thefirst aspect or the second aspect, the disperse phase including anacidic polymer is a disperse phase including polyacrylic acid or acarboxyvinyl polymer.

As a fourth aspect, in the hydrogel-forming material according to theaspect, the disperse phase (A) further includes a polyhydric alcohol.

As a fifth aspect, in the hydrogel-forming material according to thefirst aspect, the disperse phase (B) including a water-soluble acidicpolymer further includes a polyhydric alcohol.

As a sixth aspect, it relates to a method for producing a hydrogelcomprising: a step of preparing the disperse phase (A) including a lipidpeptide-based gelator, water, and a fatty acid salt as described in thefirst aspect; a step of adding the disperse phase (B) including awater-soluble acidic polymer to the disperse phase (A); and a step ofstirring the resulting mixture at room temperature and then leaving theresulting mixture still standing to form a hydrogel.

As a seventh aspect, in the method for producing a hydrogel according tothe seventh aspect, preparation of the disperse phase (A) is performedby mixing the lipid peptide-based gelator, water, and the fatty acidsalt at a high temperature with stirring and then leaving the resultingmixture to cool to reach room temperature.

As an eighth aspect, it relates to a hydrogel formed from thehydrogel-forming material as described in any one of the first aspect tothe fifth aspect.

As a ninth aspect, it relates to a premix useful in preparation of ahydrogel for use in a cosmetic or a quasi drug comprising: a lipidpeptide-based gelator consisting of at least one of a compound ofFormula (1) or a pharmaceutically usable salt thereof; water; and afatty acid salt:

(where R¹ is a C₉₋₂₃ aliphatic group, R² is a hydrogen atom or a C₁₋₄alkyl group that optionally has a C₁₋₂ branched chain, R³ is a—(CH₂)_(n)—X group, n is a number of 1 to 4, X is an amino group, aguanidine group, a —CONH₂ group, a 5-membered ring optionally containing1 to 3 nitrogen atom(s), a 6-membered ring optionally containing 1 to 3nitrogen atom(s), or a condensed heterocycle that contains a 5-memberedring and a 6-membered ring optionally containing 1 to 3 nitrogenatom(s)).

Effects of the Invention

The hydrogel-forming material of the present invention is a binarysystem constituted of a disperse phrase including a gelator and a fattyacid salt and a disperse phase including a water-soluble acidic polymer.Because of this, mixing the two phases (liquid phases) with stirringachieves an increase in viscosity, and an excellent hydrogel can beeasily obtained without formation of insoluble matters or deposits justby leaving the resulting mixture still standing at room temperature.This can ensure safety and enhanced productivity due to reduction incooling time when a hydrogel is produced in an industrial scale and canalso provide a hydrogel-forming material that is improved in terms ofoperability, cost, and consistency in quality.

The lipid peptide-based gelator used in the present invention, whenstirred with a particular fatty acid salt and water under relativelygentle conditions in terms of temperature, for example, at 80° C., canbe dispersed in water serving as a medium in a relatively short time. Inaddition, when the resulting mixture is left to cool with stirring, itis not gelled but can be kept in a liquid state (a disperse phase) evenat room temperature. Therefore, this disperse phase can be suitably usedas a gel premix material that can be stored at room temperature.

In addition, the lipid peptide-based gelator included in thehydrogel-forming material of the present invention is a syntheticlow-molecular compound that is solely composed of a lipid and a peptideand is highly safe. In addition, the fatty acid salt contained as anadditive is an additive generally used in foods, cosmetics, andpharmaceuticals. In other words, the hydrogel-forming material and thepremix of the present invention are highly safe for living organisms andextremely useful particularly in applications such as cell culturebases, biomedical materials, or cosmetics materials, when consideringthe high safety level of required in these applications.

Besides, the hydrogel-forming material and the premix of the presentinvention allow a gel to be formed by a gelation of water without using,for example, a crosslinking agent or the like that is necessary forforming a conventional synthetic polymer gel. Therefore, unreactedsubstances such as crosslinking agent are not left in the resultinghydrogel. In addition, the lipid peptide-based gelator included in thehydrogel-forming material and the premix allow a hydrogel to be formedwhen being added at an amount as small as about 1% by mass, for example,0.1 to 0.5% by mass. Accordingly, a burden to the environment or livingorganisms is small when incorporated.

The method for producing a hydrogel of the present invention allows ahydrogel to be formed by stirring two types of liquids together undercondition of room temperature. Therefore, the method is advantageous interms of enhancement in productivity (due to reduction in cooling time)and production safety, which have been regarded as an issue when scalingup the production in the conventional processes that require hightemperature condition, as well as in terms of cost. In addition, by themethod of the present invention, a hydrogel can be formed withoutcausing denaturation of additives used in cosmetics or quasi drugs,which are preferably kept away from heat. Further, since the system canbe kept uniform by stirring, the method of the present invention isadvantageous in terms of consistency in quality.

As described above, the hydrogel of the present invention can beobtained with a small amount of gelator used compared to conventionalcases and therefore can be regarded as safe to living organisms and theenvironment.

As described above, a gel obtained from a lipid peptide that is alow-molecular compound can be readily decomposed in the outsideenvironment, for example, by soil bacteria and the like when used in thesoil or by metabolic enzymes when used in living organisms, Therefore, aburden to the environment or living organisms is small.

Further, the hydrogel of the present invention can be formed at roomtemperature as described above and can incorporate an additive that canbe unfavorably affected by heat.

Besides, the hydrogel of the present invention is within the range ofweakly acidic to neutral pH values and is therefore regarded as a gelhaving a pH within the range suitable for applications such as cellculture bases, biomedical materials, and cosmetics materials.

Modes for Carrying Out the Invention

The present invention relates to a hydrogel-forming material thatincludes a disperse phase (A) including a lipid peptide-based gelatorconsisting of at least one of a compound of Formula (1) to be describedbelow in detail or a pharmaceutically usable salt thereof, water, and afatty acid salt and a disperse phase (B) that includes a water-solubleacidic polymer increasing viscosity by neutralization.

Each component will be described.

<Disperse Phase (A)>

[Lipid Peptide-Based Gelator]

The lipid peptide-based gelator used in the present invention can be acompound of Formula (1) (lipid peptide) or a pharmaceutically usablesalt thereof (a low-molecular compound having a lipid moiety serving asa hydrophobic moiety and a peptide moiety serving as a hydrophilicmoiety).

In Formula (1), R¹ is a C₉₋₂₃ aliphatic group and is preferably a linearC₁₁₋₂₃ aliphatic group that optionally contains 0 to 2 unsaturatedbonds.

Specific examples of the lipid moiety (acyl group) including R¹ and atadjacent carbonyl group can include a lauroyl group, a dodecylcarbonylgroup, a myristoyl group, a tetradecylcarbonyl group, a palmitoyl group,a margaroyl group, an oleoyl group, an elaidoyl group, a linoleoylgroup, a stearoyl group, a vaccenoyl group, an octadecylcarbonyl group,an arachidoyl group, an eicosylcarbonyl group, a behenoyl group, anerucanoyl group, a docosylcarbonyl group, a lignoceroyl group, and anervonoyl group. Particularly preferable examples thereof include alauroyl group, a myristoyl group, a palmitoyl group, a margaroyl group,a stearoyl group, an oleoyl group, an elaidoyl group, and a behenoylgroup.

In Formula (1), R² in the peptide moiety is a hydrogen atom or a C₁₋₄alkyl group that optionally contains a C₁₋₂ branched chain.

The C₁₋₄ alkyl group that optionally contains a C₁₋₂ branched chainmeans an alkyl group that contains a C₁₋₄ main chain and optionallycontains a C₁₋₂ branched chain, and specific examples thereof include amethyl group, an ethyl group, a n-propyl group, an isopropyl group, an-butyl group, an isobutyl group, a sec-butyl group, and a tert-butylgroup.

R² is preferably a hydrogen atom or a C₁₋₃ alkyl group that optionallycontains a C₁ branched chain, and is more preferably a hydrogen atom.

The C₁₋₃ alkyl group that optionally contains a C₁ branched chain meansan alkyl group that contains a C₁₋₃ main chain and optionally contains aC₁ branched chain, and specific examples thereof include a methyl group,an ethyl group, a n-propyl group, an isopropyl group, an isobutyl group,and a sec-butyl group. A methyl group, an isopropyl group, an isobutylgroup, and a sec-butyl group are preferable.

In Formula (1), R³ is a —(CH₂)_(n)—X group. In the —(CH₂)_(n)—X group, nis a number of 1 to 4, and X is an amino group, a guanidine group, a—CONH₂ group, a 5-membered ring group optionally containing 1 to 3nitrogen atom(s), a 6-membered ring group optionally containing 1 to 3nitrogen atom(s), or a condensed heterocycle group that contains a5-membered ring and a 6-membered ring optionally containing 1 to 3nitrogen atom(s).

In the —(CH₂)_(n)—X group as R³, X is preferably an amino group, aguanidino group, a carbamoyl group (—CONH₂ group), a pyrrole group, animidazole group, a pyrazole group, or an indole group, and is morepreferably an imidazole group. In the —(CH₂)_(n)—X group, n ispreferably 1 or 2 and is more preferably 1.

Accordingly, the —(CH₂)_(n)— group is preferably an aminomethyl group, a2-aminoethyl group, a 3-aminopropyl group, a 4-aminobutyl group, acarbamoylmethyl group, a 2-carbamoylethyl group, a 3-carbamoylbutylgroup, a 2-guanidinoethyl group, a 3-guanidinobutyl group, a pyrrolemethyl group, a 4-imidazole methyl group, a pyrazole methyl group, or a3-indole methyl group, is more preferably a 4-aminobutyl group, acarbamoylmethyl group, a 2-carbamoylethyl group, a 3-guanidinobutylgroup, a 4-imidazole methyl group, or a 3-indole methyl group, and isfurther preferably a 4-imidazole methyl group.

Lipid peptides that are particularly preferable as the lipidpeptide-based gelator in the compound of Formula (1) are the followingcompounds formed from a lipid moiety and a peptide moiety (a moiety ofassembled amino acids) (amino acid abbreviations are as follows: alanine(Ala), asparagine (Asn), glutamine (Gln), glycine (Gly), histidine(His), isoleucine (Ile), leucine (Leu), lysine (Lys), tryptophan (Trp),and valine (Val)): lauroyl-Gly-His, lauroyl-Gly-Gln, lauroyl-Gly-Asn,lauroyl-Gly-Trp, lauroyl-Gly-Lys, lauroyl-Ala-His, lauroyl-Ala-Gln,lauroyl-Ala-Asn, lauroyl-Ala-Trp, and lauroyl-Ala-Lys;myristoyl-Gly-His, myristoyl-Gly-Gln, myristoyl-Gly-Asn,myristoyl-Gly-Trp, myristoyl-Gly-Lys, myristoyl-Ala-His,myristoyl-Ala-Gln, myristoyl-Ala-Asn, myristoyl-Ala-Trp, andmyristoyl-Ala-Lys; palmitoyl-Gly-His, palmitoyl-Gly-Gln,palmitoyl-Gly-Asn, palmitoyl-Gly-Trp, palmitoyl-Gly-Lys,palmitoyl-Ala-His, palmitoyl-Ala-Gln, palmitoyl-Ala-Asn,palmitoyl-Ala-Trp, and palmitoyl-Ala-Lys; and stearoyl-Gly-His,stearoyl-Gly-Gln, stearoyl-Gly-Asn, stearoyl-Gly-Trp, stearoyl-Gly-Lys,stearoyl-Ala-His, stearoyl-Ala-Gln, stearoyl-Ala-Asn, stearoyl-Ala-Trp,and stearoyl-Ala-Lys.

Most preferable examples thereof include lauroyl-Gly-His andlauroyl-Ala-His; myristoyl-Gly-His and myristoyl-Ala-His;palmitoyl-Gly-His and palmitoyl-Ala-His; and stearoyl-Gly-His andstearoyl-Ala-His.

In the present invention, the ratio of the lipid peptide-based gelatorto be added is, for example, 0.01 to 30% by mass, preferably 0.02 to 10percent by mass, and more preferably 0.05 to 5 percent by mass relativeto the total mass of the hydrogel.

The lipid peptide-based gelator used in the present invention containsat least one of the compound of Formula (1) (lipid peptide) or apharmaceutically usable salt thereof, and such a compound can be usedalone or as a combination of two or more of these as a hydrogelator.

[Fatty Acid Salt]

The fatty acid salt used in the present invention can be a fatty acidsalt that is generally used as an additive in cosmetics and/orpharmaceuticals.

Examples of the fatty acid salt include butyrates, valerates, caproates,enanthates, caprylates, pelargonates, caprates, laurates, myristates,pentadecylates, palmitates, palmitoleates, margarates, stearates,oleates, vaccenates, linoleates, (9,12,15)-linolenates,(6,9,12)-linolenates, eleostearates, tuberculostearates, arachidates,arachidonates, behenates, lignocerates, nervonates, cerotates,montanates, and melissates. Laurates, myristates, palmitates, stearates,and oleates are preferable and myristates, palmitates, and stearates arefurther preferable.

The fatty acid salt is a sodium salt or a potassium salt, for example,and is particularly preferably a sodium salt.

In the present invention, the ratio of the fatty acid salt to be addedis, for example, 0.01 to 30% by mass, preferably 0.02 to 10 percent bymass, and more preferably 0.05 to 2 percent by mass relative to thetotal mass of the hydrogel.

The fatty acid salt used in the present invention contains at least onetype selected from the group consisting of the fatty acid saltsexemplified above, and such fatty acid salts can be used alone or as acombination of two or more of these.

[Preparation of Disperse Phase (A)]

The disperse phase (A) can be produced by mixing the lipid peptide-basedgelator containing at least one of the compound of Formula (1) or apharmaceutically usable salt thereof, water, and the fatty acid salt andthen stirring the resulting mixture under conditions in which thetemperature is high, for example, at room temperature or higher andlower than 100° C., preferably at 50° C. to 90° C., and more preferablyat 60° C. to 80° C., followed by leaving the resulting mixture to coolwith stirring to near room temperature.

The duration of the heating and stirring varies depending on the typesand the amounts of the lipid peptide-based gelator and an additive to beadded, and is usually about 20 minutes to about 90 minutes.

During the cooling process with stirring, an additive for cosmeticsand/or an additive for quasi drugs to be described below can be added asdesired. Among them, a polyhydric alcohol such as polyols and polymersthereof, for example, glycerin, 1,3-butylene glycol, propylene glycol,3-methyl-1,3-butanediol, 1,3-propanediol, 2-methyl-1,3-propanediol,trimethylolpropane, pentaerythritol, hexylene glycol, diglycerin,polyglycerin, diethylene glycol, polyethylene glycol, dipropyleneglycol, polypropylene glycol, and ethylene glycol-propylene glycolcopolymers can be preferably added.

The disperse phase (A) including the lipid peptide-based gelator, thefatty acid salt, and water is suitably used as a gel premix materialthat can be stored at room temperature, and can be suitably used, forexample, as a premix for preparation of cosmetics and quasi drugs, inother words, a premix material for preparation of a gel to be used incosmetics and quasi drugs. In this premix, various additives that arewell known as additives for cosmetics and/or quasi drugs, which are tobe described below, can also be added. Such a premix is also within thescope of the present invention.

<Disperse Phase (B) Including Water-Soluble Acidic Polymer>

The disperse phase (B) including a water-soluble acidic polymer as aconstituent of the hydrogel-forming material of the present invention,when mixed with the disperse phase (A), undergoes neutralization to makethe of the system neutral and weakly acidic and also increase theviscosity of the system, causing gelation of the system. This enableshydrogel preparation to be performed at room temperature with stirring.

Examples of the disperse phase including an acidic polymer include adisperse phase of polyacrylic acid and a carboxyvinyl polymer. Thepolyacrylic acid may be an acrylic acid homopolymer, an acrylicacid-methacrylic acid ester copolymer, or an acrylic acid-alkylmethacrylate copolymer.

The polyacrylic acid may be used alone or can be used as a combinationof two or more of these.

In the present invention, the concentration of the polyacrylic acid orthe carboxyvinyl polymer as a constituent of the disperse phaseincluding an acidic polymer is, for example, 0.001 to 10% by mass,preferably 0.005 to 5 percent by mass, and more preferably 0.01 to 2percent by mass relative to the total mass of the resulting hydrogel.

To the disperse phase (B) including an acidic polymer, an additive forcosmetics and/or quasi drugs, which is to be described below; can beformulated. Among them, a polyhydric alcohol such as polyols andpolymers thereof, for example, glycerin, 1,3-butylene glycol, propyleneglycol, 3-methyl-1,3-butanediol, 1,3-propanediol,2-methyl-1,3-propanediol, trimethylolpropane, pentaerythritol, hexyleneglycol, diglycerin, polyglycerin, diethylene glycol, polyethyleneglycol, dipropylene glycol, polypropylene glycol, and ethyleneglycol-propylene glycol copolymers can be preferably added.

[Other Additives]

To the gel-forming material of the present invention (the disperse phase(A), the disperse phase (B) including an acidic polymer), an additivegenerally usable as an additive for cosmetics and an additive for quasidrugs can be added where appropriate. Examples of additional ingredientssuch as physiologically active substances and functional substancesformulated in external skin preparations such as cosmetics and quasidrugs include oily base materials, moisturizers, tactile-feelingenhancers, surfactants, polymers, thickeners and gelators, solvents,propellants, antioxidants, reducing agents, oxidizing agents,preservatives, antimicrobial agents, antiseptics, chelating agents,pH-adjusters, acids, alkalis, powders, inorganic salts, ultravioletabsorbers, skin-brightening agents, vitamins and derivatives thereof,hair growth-promoting agents, blood circulation-promoters, stimulatingagents, hormones, anti-wrinkle agents, anti-aging agents, tighteningagents, cool-feeling agents, warm-feeling agents, wound-healingpromoters, abirritants, analgesics, cell activators, plant, animal, andmicrobial extracts, antipruritics, keratin-exfoliating/dissolvingagents, antiperspirants, refrigerants, styptics, enzymes, nucleic acids,perfumes, coloring agents, colorants, dyes, pigments, antiphlogistics,anti-inflammatory agents, anti-asthmatic agents, drugs for chronicobstructive pulmonary diseases, antiallergic agents, immunomodulatorsanti-infective agents, and antifungal agents.

These additional ingredients are exemplified below. Preferable examplesof the oily base materials include higher (polyhydric) alcohols such ascetanol, myristyl alcohol, oleyl alcohol, lauryl alcohol, cetostearylalcohol, stearyl alcohol, arachyl alcohol, behenyl alcohol, jojobaalcohol, chimyl alcohol, selachyl alcohol, batyl alcohol, hexyldecanol,isostearyl alcohol, 2-octyldodecanol, and dimer diols; aralkyl alcoholssuch as benzyl alcohol, and derivatives thereof; higher fatty acids suchas lauric acid, myristic acid, palmitic acid, stearic acid, isostearicacid, behenic acid, undecylene acid, 12-hydroxystearic acid, palmitoleicacid, oleic acid, linoleic acid, linolenic acid, erucic acid,docosahexaenoic acid, eicosapentaenoic acid, isohexadecanoic acid,anteisoheneicosanoic acid, branched long-chain fatty acids, dimer acids,and hydrogenated dimer acids, metal soaps thereof such as aluminum saltsthereof, calcium salts thereof, magnesium salts thereof, zinc saltsthereof, potassium salts thereof, and sodium salts thereof, andnitrogen-containing derivatives thereof such as amides thereof;hydrocarbons such as liquid paraffin (mineral oil), heavy liquidisoparaffin, light liquid isoparaffin, α-olefin oligomers,polyisobutene, hydrogenated polyisobutene, polybutene, squalane, olivesqualane, squalene, petrolatum, and solid paraffin; waxes such ascandelilla wax, carnauba wax, rice wax, Japan wax, beeswax, montan wax,ozokerite, ceresin, paraffin wax, microcrystalline wax, petrolatum,Fischer-Tropsch Wax, polyethylene wax, and ethylene-propylenecopolymers; vegetable oils such as coconut oil, palm oil, palm kerneloil, safflower oil, olive oil, castor oil, avocado oil, sesame seed oil,tea oil, evening primrose oil, wheat germ oil, macadamia oil, hazelnutoil, kukui nut oil, rose hip oil, meadowfoam oil, persic oil, tea treeoil, mint oil, maize oil, rape oil, sunflower oil, wheat germ oil,linseed oil, cottonseed oil, soybean oil, peanut oil, rice bran oil,cocoa butter, rhea butter, hydrogenated coconut oil, hydrogenated castoroil, jojoba oil, and hydrogenated jojoba oil; animal oils/fats such asbeef tallow, milk fat, horse fat, egg-yolk oil, mink oil, and turtleoil; animal waxes such as spermaceti, lanolin, and orange roughy oil;lanolins such as liquid lanolin, reduced lanolin, adsorption-purifiedlanolin, acetylated lanolin, acetylated liquid lanolin, hydroxylatedlanolin, polyoxyethylene lanolin, lanolin acid, hard lanolin acid,lanolin alcohol, acetylated lanolin alcohol, and acetylated(cetyl/lanolyl) ester; phospholipids such as lecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine,phosphatidylglycerol, phosphatidylinositol, sphingophospholipidsincluding sphingomyelin, phosphatidic acid, and lysolecithin;phospholipid derivatives such as hydrogenated soy phospholipid,partially hydrogenated soy phospholipid, hydrogenated egg-yolkphospholipid, and partially hydrogenated egg-yolk phospholipid; sterolssuch as cholesterol, dihydrocholesterol, lanosterol, dihydrolanosterol,phytosterol, and cholic acid; sapogenins; saponins; sterol esters suchas cholesteryl acetate, cholesteryl nonanoate, cholesteryl stearate,cholesteryl isostearate, cholesteryl oleate,di(cholesteryl/behenyl/octyldodecyl) N-lauroyl-L-glutamate,di(cholesteryl/octyldodecyl) N-lauroyl-L-glutamate,di(phytosteryl/behenyl/octyldodecy N-lauroyl-L-glutamate,di(phytosteryl/octyldodecyl) N-lauroyl-L-glutamate, acyl sarcosine alkylesters including isopropyl N-lauroyl sarcosinate, cholesteryl12-hydroxystearate, cholesteryl macadamiate, phytosteryl macadamiate,phytosteryl isostearate, soft lanolin acid cholesteryl ester, hardlanolin acid cholesteryl ester, branched long-chain fatty acidcholesteryl esters, and long-chain α-hydroxy fatty acid cholesterylesters; lipid complexes such as phospholipid-cholesterol complexes andphospholipid-phytosterol complexes; monoalcohol carboxylic acid esterssuch as octyldodecyl myristate, hexyldecyl myristate, octyldodecylisostearate, cetyl palmitate, octyldodecyl palmitate, cetyl octanoate,hexyldecyl octanoate, isotridecyl isononanoate, isononyl isononanoate,octyl isononanoate, isotridecyl isononanoate, isodecyl neopentanoate,isotridecyl neopentanoate, isostearyl neopentanoate, octyldodecylneodecanoate, oleyl oleate, octyldodecyl oleate, octyldodecylricinoleate, octyldodecyl lanolate, hexyldecyl dimethyloctanoate,octyldodecyl erucate, hydrogenated castor oil isostearate, ethyl oleate,ethyl avocadate, isopropyl myristate, isopropyl palmitate, octylpalmitate, isopropyl isostearate, isopropyl lanolate, diethyl sebacate,diisopropyl sebacate, dioctyl sebacate, diisopropyl adipate,dibutyloctyl sebacate, diisobutyl adipate, dioctyl succinate, andtriethyl citrate; oxyacid esters such as cetyl lactate, diisostearylmalate, and hydrogenated castor oil monoisostearate; polyhydric alcoholfatty acid esters such as glyceryl trioctanoate, glyceryl trioleate,glyceryl triisostearate, glyceryl diisostearate, caprylic/caprictriglyceride, caprylic/capric/myristic/stearic triglyceride,hydrogenated rosin triglyceride (hydrogenated ester gum), rosintriglyceride (ester gum), glyceryl behenate eicosanedioate,trimethylolpropane trioctanoate, trimethylolpropane triisostearate,neopentyl glycol dioctanoate, neopentyl glycol dicaprate,2-butyl-2-ethyl-1,3-propanediol dioctanoate, propylene glycol dioleate,pentaerythrityl tetraoctanoate, pentaerythrityl hydrogenated rosinate,ditrimethylolpropane triethylhexanoate, ditrimethylolpropane(isostearate/sebacate), pentaerythrityl triethylhexanoate,dipentaerythrityl (hydroxystearate/stearate/resinate), diglyceryldiisostearate, polyglyceryl tetraisostearate, polyglyceryl-10nonaisostearate, polyglyceryl-8 deca(erucate/isostearate/ricinoleate),(hexyldecanoic acid/sebacic acid) diglyceryl oligoester, glycoldistearate (ethylene glycol distearate), 3-methyl-1,5-pentanedioldineopentanoate, and 2,4-diethyl-1,5-pentanediol dineopentanoate; dimeracid derivatives or dimer diol derivatives such as diisopropyl dimerdilinoleate, diisostearyl dimer dilinoleate, di(isostearyl/phytosteryl)dimer dilinoleate, (phytosteryl/behenyl) dimer dilinoleate,(phytosteryl/isostearyl/cetyl/stearyl/behenyl) dinner dilinoleate, dimerdilinoleyl dimer dilinoleate, dimer dilinoleyl diisostearate, dimerdilinoleyl hydrogenated rosin condensates, hydrogenated castor oil dimerdilinoleate, and hydroxyalkyl dimer dilinoleyl ether; fatty acidalkanolamides such as coconut fatty acid monoethanolamide (cocamideMEA), coconut fatty acid diethanolamide (cocamide DEA), lauric acidmonoethanolamide (lauramide MEA), lauric acid diethanolamide (lauramideDEA), lauric acid monoisopropanolamide (lauramide MIPA), palmitic acidmonoethanolamide (palmitamide MEA), palmitic acid diethanolamide(palmitamide DEA), and coconut fatty acid methylethanolamide (cocamidemethyl MEA); silicones such as dimethicone (dimethylpolysiloxane),highly-polymerized dimethicone (highly-polymerizeddimethylpolysiloxane), cyclomethicone (cyclic dimethylsiloxane,decamethylcyclopentasiloxane), phenyl trimethicone, diphenyldimethicone, phenyl dimethicone, stearoxypropyldimethylamine,(aminoethylaminopropyl methicone/dimethicone) copolymer, dimethiconol,dimethiconol crosspolymer, silicone resins, silicone rubber,amino-modified silicones including aminopropyl dimethicone andamodimethicone, cation-modified silicones, polyether-modified siliconesincluding dimethicone copolyols, polyglycerin-modified silicones,sugar-modified silicones, carboxylic acid-modified silicones, phosphoricacid-modified silicones, sulfuric acid-modified silicones,alkyl-modified silicones, fatty acid-modified silicones, alkylether-modified silicones, amino acid-modified silicones,peptide-modified silicones, fluorine-modified silicones, cation-modifiedand polyether-modified silicones, amino-modified and polyether-modifiedsilicones, alkyl-modified and polyether-modified silicones, andpolysiloxane-oxyalkylene copolymers; and fluorine oils such asperfluorodecane, perfluorooctane, and perfluoropolyether.

Preferable examples of the moisturizers and the tactile-feelingenhancers include polyols and polymers thereof such as glycerin,1,3-butylene glycol, propylene glycol, 3-methyl-1,3-butanediol,1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane,pentaerythritol, hexylene glycol, diglycerin, polyglycerin, diethyleneglycol, polyethylene glycol, &propylene glycol, polypropylene glycol,and ethylene glycol-propylene glycol copolymers; glycol alkyl etherssuch as diethylene glycol monoethyl ether (ethoxydiglycol), ethyleneglycol monoethyl ether, ethylene glycol monobutyl ether, and diethyleneglycol dibutyl ether; water-soluble esters such as polyglyceryl-10(eicosanedioate/tetradecanedioate) and polyglyceryl-10tetradecanedioate; sugar alcohols such as sorbitol, xylitol, erythritol,mannitol, and maltitol; saccharides and derivatives thereof such asglucose, fructose, galactose, mannose, threose, xylose, arabinose,fucose, ribose, deoxyribose, maltose, trehalose, lactose, raffinose,gluconic acid, glucuronic acid, cyclodextrins (α-, β-, andγ-cyclodextrins, and modified cyclodextrins such as maltosylcyclodextrin and hydroxyalkyl cyclodextrin), β-glucan, chitin, chitosan,heparin and heparin derivatives, pectin, arabinogalactan, dextrin,dextran, glycogen, ethyl glucoside, poly(glucosylethyl methacrylate),and (glucosylethyl methacrylate) copolymer; hyaluronic acid and sodiumhyaluronate; sodium chondroitin sulfate; mucoitin sulfate, charoninsulfate, kerato sulfate, and dermatan sulfate; Tremella fuciformisextract and Tremella fuciformis polysaccharide; fucoidan; tuberosepolysaccharide and natural polysaccharides; organic acids such as citricacid, tartaric acid, and lactic acid, and salts thereof; urea andderivatives thereof; 2-pyrrolidone-5-carboxylic acid, and salts thereofincluding sodium thereof; amino acids such as betaine(trimethylglycine), proline, hydroxyproline, arginine, lysine, serine,glycine, alanine, phenylalanine, tyrosine, β-alanine, threonine,glutamic acid, glutamine, asparagine, aspartic acid, cysteine, cysteine,methionine, leucine, isoleucine, valine, tryptophan, histidine, andtaurine, and salts thereof; protein peptides, and derivative thereof;such as collagen, fish collagen, atelocollagen, gelatin, elastin,peptides derived from decomposed collagen, hydrolyzed collagen,hydroxypropylammonium chloride hydrolyzed collagen, peptides derivedfrom decomposed elastin, peptides derived from decomposed keratin,hydrolyzed keratin, peptides derived from decomposed conchiolin,hydrolyzed conchiolin, peptides derived from decomposed silk protein,hydrolyzed silk, sodium lauroyl hydrolyzed silk, peptides derived fromdecomposed soy protein, peptides derived from decomposed wheat protein,hydrolyzed wheat protein, peptides derived from decomposed casein, andacylated peptides; acylated peptides such as palmitoyl oligopeptide,palmitoyl pentapeptide, and palmitoyl tetrapeptide; silylated peptides;a culture medium of lactic acid bacteria, a yeast extract solution, aneggshell membrane protein, bovine submaxillary mucin, hypotaurine,sesame lignan glycoside, glutathione, albumin, and whey; cholinechloride and phosphoryl choline; and animal and plant extract componentssuch as a placenta extract solution, elastin, collagen, aloe extract,Hamamelis virginiana water, Luffa cylindrica water, Chamomilla recutitaextract, licorice extract, Symphytum officinale extract, silk extract,Rosa roxburghii extract, Achillea millefolium extract, Eucalyptusglobulus extract, and Melilotus officinalis extract, and ceramides suchas natural ceramides (type 1, 2, 3, 4, 5, and 6), hydroxyceramide,pseudoceramide, sphingoglycolipid, ceramide-containing extracts, andglucosylceramide-containing extracts.

Preferable examples of the surfactants include anionic surfactants,nonionic surfactants, cationic surfactants, amphoteric surfactants, andpolymer surfactants. Preferable examples of the surfactants areexemplified below. Preferable examples of the anionic surfactantsinclude fatty acid salts such as sodium laurate, sodium myristate,sodium palmitate, sodium stearate, potassium laurate, and potassiummyristate; alkyl sulfuric acid ester salts such as sodium laurylsulfate, triethanolamine lauryl sulfate, and ammonium lauryl sulfate;polyoxyethylene alkyl sulfates such as sodium laureth sulfate andtriethanolamine laureth sulfate; acyl N-methyl amino acid salts such assodium cocoyl methyl taurate, potassium cocoyl methyl taurate, sodiumlauroyl methyl taurate, sodium myristoyl methyl taurate, sodium lauroylmethylalaninate, sodium lauroyl sarcosinate, triethanolamine lauroylsarcosinate, and sodium lauroyl glutamate methylalaninate; acylaminoacid salts such as sodium cocoyl glutamate, triethanolamine cocoylglutamate, sodium lauroyl glutamate, sodium myristoyl glutamate, sodiumstearoyl glutamate, ditriethanolamine palmitoyl aspartate, andtriethanolamine cocoyl alaninate; polyoxyethylene alkyl ether acetatessuch as sodium laureth acetate; succinic acid ester salts such as sodiumlauroyl monoethanolamide succinate; fatty acid alkanolamide ethercarboxylates; acyl lactates; polyoxyethylene fatty amine sulfates; fattyacid alkanolamide sulfates; fatty acid glyceride sulfates such as sodiumglycerin hydrogenated coconut fatty acid sulfate; alkylbenzenepolyoxyethylene sulfates; olefin sulfonates such as sodium α-olefinsulfonate; alkyl sulfosuccinates such as disodium lauryl sulfosuccinateand sodium dioctyl sulfosuccinate; alkyl ether sulfosuccinates such asdisodium laureth sulfosuccinate, sodium monolauroyl monoethanolamidepolyoxyethylene sulfosuccinate, and sodium lauryl polypropylene glycolsulfosuccinate; alkylbenzene sulfonates such as sodium tetradecylbenzenesulfonate and triethanolamine tetradecylbenzene sulfonate; alkylnaphthalene sulfonates; alkane sulfonates; α-sulfofatty acid methylester salts; acyl isethionates; alkyl glycidyl ether sulfonates; alkylsulfoacetates; alkyl ether phosphoric acid ester salts such as sodiumlaureth phosphate, sodium dilaureth phosphate, sodium trilaurethphosphate, and sodium monooreth phosphate; alkyl phosphoric acid estersalts such as potassium lauryl phosphate; sodium caseinate; alkyl arylether phosphates; fatty amide ether phosphates; phospholipids such asphosphatidylglycerol, phosphatidylinositol, and phosphatidic acid; andsilicone anionic surfactants such as carboxylic acid-modified silicones,phosphoric acid-modified silicones, and sulfuric acid-modifiedsilicones. Preferable examples of the nonionic surfactants includepolyoxyethylene alkyl ethers with various numbers of polyoxyethylenesaddition such as laureths (polyoxyethylene lauryl ethers), ceteths(polyoxyethylene cetyl ethers), steareths (polyoxyethylene stearylethers), beheneths (polyoxyethylene behenyl ethers), isosteareths(polyoxyethylene isostearyl ethers), and octyldodeceths (polyoxyethyleneoctyldodecyl ethers); polyoxyethylene alkyl phenyl ethers; castor oilderivatives and hydrogenated castor oil derivatives such aspolyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil,polyoxyethylene hydrogenated castor oil monoisostearate, polyoxyethylenehydrogenated castor oil triisostearate, polyoxyethylene hydrogenatedcastor oil monopyroglutamate monoisostearate diester, andpolyoxyethylene hydrogenated castor oil maleate; polyoxyethylenephytosterol; polyoxyethylene cholesterol; polyoxyethylene cholestanol;polyoxyethylene lanolin; polyoxyethylene reduced lanolin;polyoxyethylene-polyoxypropylene alkyl ethers such aspolyoxyethylene-polyoxypropylene cetyl ether,polyoxyethylene-polyoxypropylene 2-decyltetradecyl ether,polyoxyethylene-polyoxypropylene monobutyl ether,polyoxyethylene-polyoxypropylene hydrogenated lanolin, andpolyoxyethylene-polyoxypropylene glycerin ether;polyoxyethylene-polyoxypropylene glycol; (poly)glycerin polyoxypropyleneglycols such as PPG-9 diglyceryl; glycerin fatty acid partial esterssuch as glyceryl stearate, glyceryl isostearate, glyceryl palmitate,glyceryl myristate, glyceryl oleate, glyceryl cocoate, glycerinmono-cottonseed oil fatty acid, glycerin monoerucate, glycerinsesquioleate, glycerin α,α′-oleate pyroglutamate, and glycerinmonostearate malate; polyglycerin fatty acid esters such aspolyglyceryl-2 stearate, polyglyceryl-3 stearate, polyglyceryl-4stearate, polyglyceryl-5 stearate, polyglyceryl-6 stearate,polyglyceryl-8 stearate, polyglyceryl-10 stearate, polyglyceryl-6distearate, polyglyceryl-10 distearate, polyglyceryl-2 tristearate,polyglyceryl-10 decastearate, polyglyceryl-2 isostearate, polyglyceryl-3isostearate, polyglyceryl-4 isostearate, polyglyceryl-5 isostearate,polyglyceryl-6 isostearate, polyglyceryl-8 isostearate, polyglyceryl-10isostearate, polyglyceryl-2 diisostearate (diglyceryl diisostearate),polyglyceryl-3 diisostearate, polyglyceryl-10 diisostearate,polyglyceryl-2 triisostearate, polyglyceryl-2 tetraisostearate,polyglyceryl-10 decaisostearate, polyglyceryl-2 oleate, polyglyceryl-3oleate, polyglyceryl-4 oleate, polyglyceryl-5 oleate, polyglyceryl-6oleate, polyglyceryl-8 oleate, polyglyceryl-10 oleate, polyglyceryl-6dioleate, polyglyceryl-2 trioleate, and polyglyceryl-10 decaoleate;ethylene glycol mono-fatty acid esters such as ethylene glycolmonostearate; propylene glycol mono-fatty acid esters such as propyleneglycol monostearate; pentaerythritol fatty acid partial esters; sorbitolfatty acid partial esters; maltitol fatty acid partial esters; maltitolether; sorbitan fatty acid esters such as sorbitan monooleate, sorbitanmonoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitanpenta-2-ethylhexylate diglycerol, and sorbitan tetra-2-ethylhexylatediglycerol; sugar derivative partial esters such as sucrose fatty acidesters, methyl glucoside fatty acid esters, and trehalose undecylenoate;alkyl glucosides such as caprylyl glucoside; alkyl polyglycosides;lanolin alcohol; reduced lanolin; polyoxyethylene fatty acid monoestersand polyoxyethylene fatty acid diesters such as polyoxyethylenedistearate, polyethylene glycol diisostearate, polyoxyethylenemonooleate, and polyoxyethylene dioleate; polyoxyethylene-propyleneglycol fatty acid esters; polyoxyethylene glycerin fatty acid esterssuch as polyoxyethylene glycerin monostearate, polyoxyethylene glycerinmonoisostearate, and polyoxyethylene glycerin triisostearate;polyoxyethylene sorbitan fatty acid esters such as polyoxyethylenesorbitan monooleate, polyoxyethylene sorbitan monostearate,polyoxyethylene sorbitan monooleate, and polyoxyethylene sorbitantetraoleate; polyoxyethylene sorbitol fatty acid esters such aspolyoxyethylene sorbitol monolaurate, polyoxyethylene sorbitolmonooleate, polyoxyethylene sorbitol pentaoleate, and polyoxyethylenesorbitol monostearate; polyoxyethylene methyl glucoside fatty acidesters; polyoxyethylene alkyl ether fatty acid esters;polyoxyethylene-modified animal and vegetable oils/fats such aspolyoxyethylene sorbitol beeswax; alkyl glyceryl ethers such asisostearyl glyceryl ether, chimyl alcohol, selachyl alcohol, and batylalcohol; polyhydric alcohol alkyl ethers; polyoxyethylene alkylamines;tetrapolyoxyethylene/tetrapolyoxypropylene-ethylenediamine condensates;natural surfactants such as saponins and sophorolipid; polyoxyethylenefatty acid amides; fatty acid alkanolamides such as coconut fatty acidmonoethanolamide (cocamide MEA), coconut fatty acid diethanolamide(cocamide DEA), lauric acid monoethanolamide (lauramide MEA), lauricacid diethanolamide (lauramide DEA), lauric acid monoisopropanolamide(lauramide MIPA), palmitic acid monoethanolamide (palmitamide MEA),palmitic acid diethanolamide (palmitamide DEA), and coconut fatty acidmethylethanolamide (cocamide methyl MEA); alkyl dimethylamine oxidessuch as lauramine oxide, cocamine oxide, stearamine oxide, andbehenamine oxide; alkyl ethoxy dimethylamine oxides; polyoxyethylenealkyl mercaptans; and silicone nonionic surfactants such aspolyether-modified silicones including dimethicone copolyols,polysiloxane-oxyalkylene copolymers, polyglycerin-modified silicones,and sugar-modified silicones. Preferable examples of the cationicsurfactants include alkyl trimethylammonium chlorides such asbehentrimonium chloride, steartrimonium chloride, cetrimonium chloride,and lauryltrimonium chloride; alkyl trimethylammonium bromides such asstearyltrimonium bromide; dialkyl dimethylammonium chlorides such asdistearyldimonium chloride and dicocodimonium chloride; fatty acid amideamines such as stearamide propyldimethylamine and stearamideethyldiethylamine, and salts thereof; alkyl ether amines such asstearoxypropyldimethylamine, and salts and quaternary salts thereof;fatty acid amide quaternary ammonium salts such as branched long-chainfatty acid (12 to 31) aminopropylethyldimethylammonium ethyl sulfatesand lanolin fatty acid aminopropylethyldimethylammonium ethyl sulfate;polyoxyethylene alkylamines, and salts and quaternary salts thereof;alkylamine salts; fatty acid amide guanidium salts; alkyl ether ammoniumsalts; alkyl trialkylene glycol ammonium salts; benzalkonium salts;benzethonium salts; pyridinium salts such as cetylpyridinium chloride;imidazolinium salts; alkyl isoquinolinium salts; dialkyl morpholiniumsalts; polyamine fatty acid derivatives; and silicone cationicsurfactants such as amino-modified silicones including aminopropyldimethicone and amodimethicone, cation-modified silicones,cation-modified and polyether-modified silicones, and amino-modified andpolyether-modified silicones. Preferable examples of the amphotericsurfactants include N-alkyl-N,N-dimethylamino acid betaines such aslauryl betaine (lauryl dimethylaminoacetic acid betaine); fatty acidamide alkyl-N,N-dimethylamino acid betaines such as cocamide propylbetaine and lauramide propyl betaine; imidazoline-type betaines such assodium cocoamphoacetate and sodium lauroamphoacetate; alkylsulfobetaines such as alkyl dimethyltaurines; sulfuric acid-typebetaines such as alkyl dimethylamino ethanol sulfuric acid esters;phosphoric acid-type betaines such as alkyl dimethylamino ethanolphosphoric acid esters; phospholipids such as phosphatidylcholine,phosphatidylethanolamine, phosphatidylserine, sphingophospholipidsincluding sphingomyelin, lysolecithin, hydrogenated soy phospholipid,partially hydrogenated soy phospholipid, hydrogenated egg-yolkphospholipid, partially hydrogenated egg-yolk phospholipid andhydroxylated lecithin; and silicone amphoteric surfactants. Preferableexamples of the polymer surfactants include polyvinyl alcohol, sodiumalginate, starch derivatives, tragacanth gum, and acrylic acid-alkylmethacrylate copolymers; and various silicone surfactants.

Preferable examples of the polymers, the thickeners, and the gelatorsinclude guar gum, locust bean gum, quince seed, carrageenan, galactan,gum arabic, tara gum, tamarind, furcellaran, karaya gum, Abelmoschusmanihot, cara gum, tragacanth gum, pectin, pectic acid and salts thereofincluding a sodium salt thereof, alginic acid and salts thereofincluding a sodium salt thereof, and mannan; starches such as ricestarch, corn starch, potato starch, and wheat starch; xanthan gum,dextran, succinoglucan, curdlan, hyaluronic acid and salts thereof,xanthan gum, pullulan, gellan gum, chitin, chitosan, agar, brown algaeextract, chondroitin sulfate, casein, collagen, gelatin, and albumin;cellulose and derivatives thereof such as methylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropyl methylcellulose, carboxymethylcellulose and salts thereofincluding sodium thereof, methylhydroxypropylcellulose, sodium cellulosesulfate, dialkyl dimethylammonium sulfate cellulose, crystallinecellulose, and cellulose powder; starch derivatives such as solublestarch, starch polymers including carboxymethyl starch,methylhydroxypropyl starch, and methyl starch, starchhydroxypropyltrimonium chloride and aluminum corn starchoctenylsuccinate; alginic acid derivatives such as sodium alginate andpropylene glycol alginic acid ester; polyvinylpyrrolidone (PVP),polyvinyl alcohol (PVA), vinylpyrrolidone-vinyl alcohol copolymers, andpolyvinyl methyl ether; polyethylene glycol, polypropylene glycol, andpolyoxyethylene-polyoxypropylene copolymers; amphoteric methacrylic acidester copolymers such as (methacryloyloxethylcarboxy betaine/alkylmethacrylate) copolymers and (acrylate/stearyl acrylate/ethylamine oxidemethacrylate) copolymers; (dimethicone/vinyl dimethicone) crosspolymer,(alkyl acrylate/diacetone acrylamide) copolymer, and (alkylacrylate/diacetone acrylamide) copolymer AMP; partially-saponifiedpolyvinyl acetate and maleic acid copolymers; vinylpyrrolidone-dialkylaminoalkyl methacrylate copolymers; acrylic resin alkanolamines;polyesters and water-dispersable polyesters; polyacrylamides;polyacrylic acid ester copolymers such as ethyl polyacrylate,carboxyvinyl polymers, polyacrylic acid and salts thereof including asodium salt thereof, acrylic acid-methacrylic acid ester copolymers;acrylic acid-alkyl methacrylate copolymers; cationized celluloses suchas polyquaternium-10, diallyldimethylammonium chloride-acrylamidecopolymers such as polyquaternium-7, acrylicacid-diallyldimethylammonium chloride copolymers such aspolyquaternium-22, acrylic acid-diallyldimethylammoniumchloride-acrylamide copolymers such as polyquaternium-39, acrylicacid-cationized methacrylic acid ester copolymers, acrylicacid-cationized methacrylic acid amide copolymers, acrylic acid-methylacrylate-methacrylamide propyltrimethylammonium chloride copolymers suchas polyquaternium-47, and methacryloyl chloride choline ester polymers;cationized polysaccharides such as cationized oligosaccharides,cationized dextran, and guar hydroxypropyltrimonium chloride;polyethyleneimines; cationic polymers; polymers of2-methacryloyloxyethylphosphorylcholine such as polyquaternium-51, andcopolymers thereof with butyl methacrylate copolymer and the like;polymer emulsions such as acrylic resin emulsions, ethyl polyacrylateemulsions, polyacrylic alkyl ester emulsions, polyvinyl acetate resinemulsions, natural rubber latex, and synthetic latex; nitrocellulose;polyurethanes and various copolymers thereof; various silicones; varioussilicone copolymers such as acrylic-silicone graft copolymers; variousfluoropolymers; 12-hydroxystearic acid and salts thereof; dextrin fattyacid esters such as dextrin palmitate and dextrin myristate; and silicicanhydride, fumed silica (silicic anhydride ultrafine particles),magnesium aluminum silicate, magnesium sodium silicate, metal soaps,metal dialkyl phosphates, bentonite, hectorite, organo-modified claymineral, sucrose fatty acid esters, and fructooligosaccharide fatty acidesters. Among them, cellulose and derivatives thereof, alginic acid andsalts thereof, polyvinyl alcohol, hyaluronic acid and salts thereof, andcollagen are preferable.

Preferable examples of the solvents and the propellants include loweralcohols such as ethanol, 2-propanol (isopropyl alcohol), butanol, andisobutyl alcohol; glycols such as propylene glycol, 1,3-butylene glycol,diethylene glycol, dipropylene glycol, and isopentyldiol; glycol etherssuch as diethylene glycol monoethyl ether (ethoxydiglycol), ethyleneglycol monoethyl ether, ethylene glycol monobutyl ether, triethyleneglycol monoethyl ether, diethylene glycol diethyl ether, diethyleneglycol dibutyl ether, propylene glycol monoethyl ether, and dipropyleneglycol monoethyl ether; glycol ether esters such as ethylene glycolmonoethyl ether acetate, diethylene glycol monoethyl ether acetate, andpropylene glycol monoethyl ether acetate; glycol esters such asdiethoxyethyl succinate and ethylene glycol disuccinate; benzyl alcohol,benzyloxyethanol, propylene carbonate, dialkyl carbonate, acetone, ethylacetate, and N-methylpyrrolidone; toluene; fluorocarbon andnext-generation fron; and propellants such as LPG, dimethyl ether, andcarbon dioxide gas.

Preferable examples of the antioxidants include tocopherol (vitamin E)and tocopherol derivatives such as tocopherol acetate; BHT and BHA;gallic acid derivatives such as propyl gallate; vitamin C (ascorbicacid) and/or derivatives thereof; erythorbic acid and derivativesthereof; sulfites such as sodium sulfite; hydrogen sulfites such assodium hydrogen sulfite; thiosulfates such as sodium thiosulfate;hydrogen metasulfites; thiotaurine and hypotaurine; and thioglycerol,thiourea, thioglycolic acid, and cysteine hydrochloride.

Preferable examples of the reducing agents include thioglycolic acid,cysteine, and cysteamine.

Preferable examples of the oxidizing agents include a hydrogen peroxidesolution, ammonium persulfate, sodium bromate, and percarbonic acid.

Preferable examples of the preservatives, the antimicrobial agents, andthe antiseptics include hydroxybenzoic acids and salts and estersthereof such as methylparaben, ethylparaben, propylparaben, andbutylparaben; salicylic acid; sodium benzoate; phenoxyethanol;isothiazolinone derivatives such as methylchloroisothiazolinone andmethylisothiazolinone; imidazolinium urea; dehydroacetic acid and saltsthereof; phenols; halogenated bisphenols such as triclosan, acid amides,and quaternary ammonium salts; trichlorocarbanilide, zinc pyrithione,benzalkonium chloride, benzethonium chloride, sorbic acid,chlorhexidine, chlorhexidine gluconate, halocarban, hexachlorophene, andhinokitiol; phenol and other phenols such as isopropylphenol, cresol,thymol, p-chlorophenol, phenylphenol, and sodium phenylphenolate; andphenylethyl alcohol, photosensitive dyes, antimicrobial zeolite, and asilver ion.

Preferable examples of the chelating agents include edetates(ehylenediamine tetraacetates) such as EDTA, EDTA-2Na, EDTA-3Na, andEDTA-4Na; hydroxyethylethylenediaminetriacetates such as HEDTA-3Na;pentetates (diethylenetriaminepentaacetate); phytic acid; phosphonicacids such as etidronic acid, and salts thereof including sodium saltsthereof; sodium oxalate; polyamino acids such as polyaspartic acid andpolyglutamic acid; sodium polyphosphate, sodium metaphosphate, andphosphoric acid; and sodium citrate, citric acid, alanine,dihydroxyethylglycine, gluconic acid, ascorbic acid, succinic acid, andtartaric acid.

Preferable examples of the pH-adjusters, acids, and alkalis includecitric acid, sodium citrate, lactic acid, sodium lactate, potassiumlactate, glycolic acid, succinic acid, acetic acid, sodium acetate,malic acid, tartaric acid, fumaric acid, phosphoric acid, hydrochloricacid, sulfuric acid, monoethanolamine, diethanolamine, triethanolamine,isopropanolamine, triisopropanolamine, 2-amino-2-methyl-1,3-propanediol,2-amino-2-hydroxymethyl-1,3-propanediol, arginine, sodium hydroxide,potassium hydroxide, an aqueous ammonia solution, guanidine carbonate,and ammonium carbonate.

Preferable examples of the powders include inorganic powders of varioussizes and shapes such as mica, talc, kaolin, sericite, montmorillonite,kaolinite, mica, muscovite, phlogopite, synthetic mica, lepidolite,biotite, vermiculite, magnesium carbonate, calcium carbonate, aluminumsilicate, barium silicate, calcium silicate, magnesium silicate,strontium silicate, metal tungstates, magnesium, zeolite, bariumsulfate, calcined calcium sulfate, calcium phosphate, fluorapatite,hydroxyapatite, ceramic powder, bentonite, smectite, clay, mud, metalsoaps (zinc myristate, calcium palmitate, and aluminum stearate, forexample), calcium carbonate, red iron oxide, yellow iron oxide, blackiron oxide, ultramarine, prussian blue, carbon black, titanium oxide,titanium oxide fine particles and titanium oxide ultrafine particles,zinc oxide, zinc oxide fine particles and zinc oxide ultrafineparticles, alumina, silica, fumed silica (silicic anhydride ultrafineparticles), titanated mica, fish scale guanine, boron nitride,photochromic pigments, synthetic fluorophlogopite, fine-particlecomposite powders, gold, and aluminum, and these inorganic powders thatare treated with a silicone such as hydrogen silicone and cyclichydrogen silicone or are otherwise treated with various surface-treatingagents such as silane coupling agents and titanium coupling agents tohydrophobize or hydrophilize these inorganic powders; and organicpowders, surface-treated organic powders, and organic-inorganiccomposite powders of various sizes and shapes such as starch, cellulose,nylon powder, polyethylene powder, polymethyl methacrylate powder,polystyrene powder, styrene-acrylate copolymer resin powder, polyesterpowder, benzoguanamine resin powder, polyethyleneterephthalate/polymethyl methacrylate-laminated powder, polyethyleneterephthalate/aluminum/epoxy-laminated powder, urethane powder, siliconepowder, and Teflon (registered trademark) powder.

Preferable examples of the inorganic salts include sodiumchloride-containing salts such as common salt, regular salt, rock salt,sea salt, and natural salt; potassium chloride, aluminum chloride,calcium chloride, magnesium chloride, bittern, zinc chloride, andammonium chloride; sodium sulfate, aluminum sulfate, aluminum potassiumsulfate (alum), aluminum ammonium sulfate, barium sulfate, calciumsulfate, potassium sulfate, magnesium sulfate, zinc sulfate, ironsulfate, and copper sulfate; and sodium phosphates such as mono-, di-,and trisodium phosphates, potassium phosphates, calcium phosphates, andmagnesium phosphates.

Preferable examples of the ultraviolet absorbers include benzoate-basedultraviolet absorbers such p-aminobenzoic acid, p-aminobenzoic acidmonoglycerin ester, N,N-dipropoxy p-aminobenzoic acid ethyl ester,N,N-diethoxy p-aminobenzoic acid ethyl ester, N,N-dimethylp-aminobenzoic acid ethyl ester, N,N-dimethyl p-aminobenzoic acid butylester, and N,N-dimethyl p-aminobenzoic acid ethyl ester;anthranilate-based ultraviolet absorbers such ashomomenthyl-N-acetylanthranilate; salicylate-based ultraviolet absorberssuch as salicylic acid and a sodium salt thereof, amyl salicylate,menthyl salicylate, homomenthyl salicylate, octyl salicylate, phenylsalicylate, benzyl salicylate, and p-isopropanolphenyl salicylate;cinnamate-based ultraviolet absorbers such as octyl cinnamate,ethyl-4-isopropyl cinnamate, methyl-2,5-diisopropyl cinnamate,ethyl-2,4-diisopropyl cinnamate, methyl-2,4-diisopropyl cinnamate,propyl-p-methoxy cinnamate, isopropyl-p-methoxy cinnamate,isoamyl-p-methoxy cinnamate, 2-ethylhexyl p-methoxy cinnamate (octylp-methoxy cinnamate), 2-ethoxyethyl-p-methoxy cinnamate (cinoxate),cyclohexyl-p-methoxy cinnamate, ethyl-α-cyano-β-phenyl cinnamate,2-ethylhexyl α-cyano-β-phenyl cinnamate (octocrylene), glycerylmono-2-ethylhexanoyl-di-p-methoxy cinnamate, and ferulic acid andderivatives thereof; benzophenone-based ultraviolet absorbers such as2,4-dihydroxybenzophenone, 2,2′-dihydroxy-4-methoxybenzophenone,2,2′-dihydroxy-4,4′-dimethoxybenzophenone,2,2′,4,4′-tetrahydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone(oxybenzone-3), 2-hydroxy-4-methoxy-4′-methylbenzophenone,2-hydroxy-4-methoxybenzophenone-5-sulfonate, 4-phenylbenzophenone,2-ethylhexyl-4′-phenyl-benzophenone-2-carboxylate,2-hydroxy-4-n-octoxybenzophenone, and 4-hydroxy-3-carboxybenzophenone;3-(4′-methylbenzylidene)-d,l-camphor and 3-benzylidene-d,l-camphor;2-phenyl-5-methylbenzoxazole; 2,2′-hydroxy-5-methylphenylbenzotriazole;2-(2′-hydroxy-5′-tert-octylphenyl)benzotriazole;2-(2′-hydroxy-5′-methylphenylbenzotriazole; dibenzalazines;dianisoylmethane; 5-(3,3-dimethyl-2-norbornylidene)-3-pentan-2-one;dibenzoylmethane derivatives such as4-tert-butylmethoxydibenzoylmethane; octyl triazone; urocanic acid, andurocanic acid derivatives such as ethyl urocanate; and2-(2′-hydroxy-5′-methylphenyl)benzotriazole,1-(3,4-dimethoxyphenyl)-4,4-dimethyl-1,3-pentanedione, hydantoinderivatives such as 2-ethylhexyl dimethoxybenzylidene dioxoimidazolidinepropionate, phenylbenzimidazole sulfonic acid, terephthalylidenedicamphor sulfonic acid, drometrizole trisiloxane, methyl anthranilate,rutin and derivatives thereof, and orizanol and derivatives thereof.

Preferable examples of the skin-brightening agents include hydroquinoneglycosides such as arbutin and α-arbutin, and esters thereof; ascorbicacid and ascorbic acid derivatives such as ascorbyl phosphate saltsincluding sodium ascorbyl phosphate and magnesium ascorbyl phosphate,ascorbyl fatty acid esters including ascorbyl tetraisopalmitate,ascorbic acid alkyl ethers including ascorbic acid ethyl ether, ascorbicacid glucosides including ascorbic acid 2-glucoside and fatty acidesters thereof, ascorbyl sulfurate, and tocopheryl ascorbyl phosphate;and kojic acid, ellagic acid, tranexamic acid and derivatives thereof,ferulic acid and derivatives thereof, placenta extract, glutathione,orizanol, butyl resorcinol, and plant extracts such as oil-solubleChamomilla recutita extract, oil-soluble licorice extract, Tamarixchinensis extract, and Saxifraga sarmentosa extract.

Preferable examples of the vitamins and derivatives thereof include thevitamin A group such as retinol, retinol acetate, and retinol palmitate;the vitamin B group such as thiamine hydrochloride, thiamine sulfate,riboflavin, riboflavin acetate, pyridoxine hydrochloride, pyridoxinedioctanoate, pyridoxine dipalmitate, flavin adenine dinucleotide,cyanocobalamine, folic acids, nicotinic acids such as nicotinamide andbenzyl nicotinate, and cholines; the vitamin C group such as ascorbicacid and salts thereof including sodium thereof; vitamin D; the vitaminE group such as α, β-, γ-, and δ-tocopherols; other vitamins such aspantothenic acid and biotin; ascorbic acid derivatives such as ascorbylphosphate salts including ascorbyl phosphate sodium salt and ascorbylphosphate magnesium salt, ascorbyl fatty acid esters including ascorbyltetraisopalmitate, ascorbyl stearate, ascorbyl palmitate, and ascorbyldipalmitate, ascorbic acid alkyl ethers including ascorbic acid ethylether, ascorbic acid glucosides including ascorbic acid 2-glucoside andfatty acid esters thereof, and tocopheryl ascorbyl phosphate; andvitamin derivatives such as tocopherol derivatives including tocopherolnicotinate, tocopherol acetate, tocopherol linoleate, tocopherolferulate, and tocopherol phosphate, tocotrienol, and other variousvitamin derivatives.

Preferable examples of the hair growth-promoting agents, the bloodcirculation-promoters, and the stimulating agents include plant extractsand tinctures such as Swertia herb extract, Capsicum frutescenstincture, ginger tincture, ginger extract, and cantharides tincture; andcapsaicin, nonylic acid vanillylamide, zingerone, ichthammol, tannicacid, borneol, cyclandelate, cinnarizine, tolazoline, acetylcholine,verapamil, cepharanthine, γ-orizanol, vitamin E and derivatives thereofincluding tocopherol nicotinate and tocopherol acetate, γ-orizanol,nicotinic acid and derivatives thereof including nicotinamide, benzylnicotinate, inositol hexanicotinate, and nicotinic alcohol, allantoin,Kankoso 301, Kankoso 401, carpronium chloride, pentadecanoic acidmonoglyceride, flavanonol derivatives, stigmasterol and stigmastanol andglycosides thereof, and minoxidil.

Preferable examples of the hormones include estradiol, estrone,ethynylestradiol, cortisone, hydrocortisone, and prednisone. Preferableexamples of other substances with drug efficacy such as the anti-wrinkleagents, the anti-aging agents, the tightening agents, the cool-feelingagents, the warm-feeling agents, the wound-healing promoters, theabirritants, the analgesics, and the cell activators include retinols,retinoic acids, and tocopheryl retinoate; lactic acid, glycolic acid,gluconic acid, fruit acid, and salicylic acid and derivatives thereofincluding glycosides thereof and esters thereof, and α- and β-hydroxyacids and derivatives thereof such as hydroxycapric acid, long-chainα-hydroxy fatty acids, long-chain α-hydroxy fatty acid cholesterylesters; γ-aminobutyric acid and γ-amino-β-hydroxybutyric acid;carnitine; carnosine; creatine; ceramides and sphingosines; caffeine,xanthine, and the like and derivatives thereof; antioxidizing agents andactive oxygen scavengers such as coenzyme Q10, carotin, lycopene,astaxanthin, lutein, α-lipoic acid, colloidal platinum nanoparticles,and fullerenes; catechins; flavones such as quercetin; isoflavones;gallic acid and sugar ester derivatives thereof; polyphenols such astannin, sesamin, proanthocyanidin, chlorogenic acid, and applepolyphenol; rutin and derivatives thereof including glycosides thereof;hesperidin and derivatives thereof including glycosides thereof; lignanglycoside; licorice extract-related substances such as glabridin,glabrene, liquiritin, and isoliquiritin; lactoferrin; shogaol andgingerol; perfume substances such as menthol and cedrol, and derivativesthereof; capsaicin, vanillin, and the like and derivatives thereof;insect repellents such as diethyltoluamide; and complexes ofphysiologically active substances and cyclodextrins.

Preferable examples of the plant, animal, and microbial extracts includeextracts such as iris extract, Angelica keiskei extract, Thujopsisdolabrata extract, asparagus extract, avocado extract, Hydrangea serrataextract, almond extract, Althaea officinalis extract, Arnica montanaextract, aloe extract, apricot extract, apricot kernel extract, Gingkobiloba extract, Artemisia capillaris flower extract, fennel seedextract, turmeric root extract, oolong tea extract, Arctostaphylosuva-ursi leaf extract, Rosa multiflora fruit extract, Echinaceaangustifolia leaf extract, Isodonis japonicus extract, Scutellariabaicalensis extract, Phellodendron amurense bark extract, Coptisjaponica root extract, Hordeum vulgare extract, Panax ginseng extract,Hypericum perforatum extract, Lamium album extract, Ononis spinosaextract, Nasturtium officinale extract, orange extract, dried sea waterresidues, seaweed extract, Persimmon leaf extract, Pyracantha fortuneanaextract, hydrolyzed elastin, hydrolyzed wheat powder, hydrolyzed silk,Pueraria lobata root extract, Chamomilla recutita extract, oil-solubleChamomilla recutita extract, Daucus carota sativa extract, Artemisiacapillaris extract, Avena fatua extract, carcade extract, licoriceextract, oil-soluble licorice extract, kiwi fruit extract, kiou extract,Auricularia auricula-judae extract, Cinchona succirubra extract,cucumber extract, Paulownia tomentosa leaf extract, guanosine, guavaextract, Sophora angustifolia extract, gardenia extract, Sasa veitchiiextract, Sophora angustifolia extract, walnut extract, chestnut extract,grapefruit extract, Clematis vitalba extract, black rice extract, blacksugar extract, black vinegar, Chlorella vulgaris extract, Morus albaextract, Gentiana lutea extract, Geranium thunbergii extract, black teaextract, yeast extract, magnolia bark extract, coffee seed extract,Arctium lappa root extract, rice extract, fermented rice extract,fermented rice bran extract, rice germ oil, Symphytum officinaleextract, collagen, Vaccinium vitis-idaea extract, Asarum sieboldiextract, Bupleurum falcatum extract, umbilical extract, saffron extract,salvia extract, Saponaria officinalis extract, sasa extract, Crataeguscuneata fruit extract, Bombyx mori excrementum extract, Zanthoxylumpiperitum extract, Corthellus shiitake extract, Rehmannia glutinosaextract, Lithospermum erythrorhizon root extract, Perilla ocymoidesextract, Tilia cordata extract, Spiraea ulmaria extract, jatoba extract,Paeonia albiflora extract, ginger extract, Acorus calamus root extract,Betula platyphylla japonica extract, Tremella fuciformis extract,Equisetum arvense extract, stevia extract, stevia fermentation product,Tamarix chinensis extract, Hedera helix extract, Crataegus oxyacanthaextract, Sambucus nigra extract, Achillea millefolium extract, Menthapiperita extract, sage extract, Malva sylvestris extract, Cnidiumofficinale extract, Swertia herb extract, Morus alba root extract, Rheumextract, soybean extract, Zizyphus jujuba extract, thyme extract,dandelion extract, lichen extract, Camellia sinensis leaf extract, cloveextract, Imperata cylindrica extract, Citrus unshiu peel extract, teatree oil, Rubus suavissimus extract, Capsicum frutescens extract,Angelica acutiloba extract, Calendula officinalis extract, Prunuspersica kernel extract, Citrus aurantium amara peel extract, Houttuyniacordata extract, tomato extract, natto extract, carrot extract, garlicextract, Rosa carina extract, hibiscus extract, Ophiopogon japonicusroot extract, Nelumbo nucifera extract, parsley extract, birch extract,honey, Hamamelis virginiana extract, Parietaria officinalis extract,Isodonis japonicus extract, bisabolol, Chamaecyparis obtusa extract,Bifidobacterium extract, Eriobotrya japonica extract, Tussilago farfaraextract, Petasites japonicus flower stalk extract, Poria cocossclerotium extract, Ruscus aculeatus extract, grape extract, grape seedextract, propolis, Luffa cylindrica extract, safflower extract,peppermint extract, Tilia miqueliana extract, Paeonia suffruticosa rootextract, hops extract, Rosa rugosa flower extract, Pinus sylvestris coneextract, horse chestnut extract, Lysichiton camtschatcense extract,Sapindus mukurossi peel extract, Melissa officinalis extract, Nemacystusdecipiens extract, peach extract, Centaurea cyanus extract, Eucalyptusglobulus extract, Saxifraga sarmentosa extract, Citrus junos extract,lily extract, Coix lacryma-jobi seed extract, Artemisia princepsextract, lavender extract, green tea extract, egg shell membraneextract, apple extract, rooibos tea extract, Ganoderma lucidum extract,lettuce extract, lemon extract, forsythia extract, Astragalus sinicusextract, rose extract, rosemary extract, Anthemis nobilis extract, royaljelly extract, and Sanguisorba officinalis root extract.

Examples of the antipruritics include diphenhydramine hydrochloride,chlorpheniramine maleate, camphor, and substance P inhibitors.

Examples of the keratin-exfoliating/dissolving agents include salicylicacid, sulfur, resorcin, selenium sulfide, and pyridoxine.

Examples of the antiperspirants include aluminum chlorohydrate, aluminumchloride, zinc oxide, and zinc p-phenolsulfonate.

Examples of the refrigerants include menthol and methyl salicylate.

Examples of the styptics include citric acid, tartaric acid, lacticacid, aluminum potassium sulfite, and tannic acid.

Examples of the enzymes include superoxide dismutases, catalases,lysozyme chloride, lipases, papain, pancreatin, and proteases.

Preferable examples of the nucleic acids include ribonucleic acid andsalts thereof, deoxyribonucleic acid and salts thereof, and adenosinetriphosphate disodium.

Preferable examples of the perfumes include synthetic perfumes andnatural perfumes such as acetyl cedrene, amylcinnamaldehyde, allylamylglycolate, β-ionone, Iso E Super, isobutylquinoline, iris oil, irone,indole, ylang-ylang oil, undecanal, undecenal, γ-undecalactone,estragole, eugenol, oakmoss, opoponax resinoid, orange oil, eugenol,aurantiol, galaxolide, carvacrol, L-carvone camphor, canon, carrot seedoil, clove oil, methyl cinnamate, geraniol, geranyl nitrile, isobornylacetate, geranyl acetate, dimethylbenzylcarbinyl acetate, styralylacetate, cedryl acetate, terpinyl acetate, p-t-butylcyclohexyl acetate,vetiveryl acetate, benzyl acetate, linalyl acetate, isopentylsalicylate, benzyl salicylate, sandalwood oil, santalol, cyclamenaldehyde, cyclopentadecanolide, methyl dihydrojasmonate,dihydromyrcenol, jasmine absolute, jasmin lactone, cis-jasmone, citral,citronellol, citronellal, cinnamon bark oil, 1,8-cineole,cinnamaldehyde, styrax resinoid, cedarwood oil, cedrene, cedrol, celeryseed oil, thyme oil, damascone, damascenone, thymol, tuberose absolute,decanal, decalactone, terpineol, γ-terpinen, triplal, nerol, nonanal,2,6-nonadienol, nonalactone, patchouli alcohol, vanilla absolute,vanillin, basil oil, patchouli oil, hydroxycitronellal, α-pinene,piperitone, phenethyl alcohol, phenylacetaldehyde, petitgrain oil,hexylcinnamaldehyde, cis-3-hexenol, Peru balsam, vetiver oil, vetiverol,peppermint oil, pepper oil, heliotropin, bergamot oil, benzyl benzoate,borneol, mil resinoid, musk ketone, methyl nonyl acetaldehyde, γ-methylionone, menthol, L-menthol, L-menthone, Eucalyptus globulus oil,β-ionone, lime oil, lavender oil, D-limonene, linalool, lyral, lilial,lemon oil, rose absolute, rose oxide, rose oil, rosemary oil, andvarious essential oils, and various perfume blends.

Preferable examples of the coloring agents, the colorants, the dyes, andthe pigments include Japanese cosmetic colors such as Brown No. 201,Black No. 401, Violet No. 201, Violet No. 401, Blue No. 1, Blue No. 2,Blue No. 201, Blue No. 202, Blue No. 203, Blue No. 204, Blue No. 205,Blue No. 403, Blue No. 404, Green No. 201, Green No. 202, Green No. 204,Green No. 205, Green No. 3, Green No. 401, Green No. 402, Red No. 102,Red No. 104-1, Red No. 105-1, Red No. 106, Red No. 2, Red No. 201, RedNo. 202, Red No. 203, Red No. 204, Red No. 205, Red No. 206, Red No.207, Red No. 208, Red No. 213, Red No. 214, Red No. 215, Red No. 218,Red No. 219, Red No. 220, Red No. 221, Red No. 223, Red No. 225, Red No.226, Red No. 227, Red No. 228, Red No. 230-1, Red No. 230-2, Red No.231, Red No. 232, Red No. 3, Red No. 401, Red No. 404, Red No. 405, RedNo. 501, Red No. 502, Red No. 503, Red No. 504, Red No. 505, Red No.506, Orange No. 201, Orange No. 203, Orange No. 204, Orange No. 205,Orange No. 206, Orange No. 207, Orange No. 401, Orange No. 402, OrangeNo. 403, Yellow No. 201, Yellow No. 202-1, Yellow No. 202-2, Yellow No.203, Yellow No. 204, Yellow No. 205, Yellow No. 4, Yellow No. 401,Yellow No. 402, Yellow No. 403-1, Yellow No. 404, Yellow No. 405, YellowNo. 406, Yellow No. 407, and Yellow No. 5; other acid dyes such as AcidRed No. 14; basic dyes such as Arianor Sienna Brown, Arianor Madder Red,Arianor Steel Blue, and Arianor Straw Yellow; nitro dyes such as HCYellow No. 2, HC Yellow No. 5, HC Red No. 3,4-hydoxypropylamino-3-nitrophenol,N,N′-bis(2-hydroxyethyl)-2-nitro-p-phenylenediamine, HC Blue No. 2, andBasic Blue No. 26; disperse dyes; inorganic white pigments such astitanium dioxide and zinc oxide; inorganic red pigments such as ironoxide (red iron oxide) and iron titanate; inorganic brown pigments suchas γ-iron oxide; inorganic yellow pigments such as yellow iron oxide andochre; inorganic black pigments such as black iron oxide and lower-ordertitanium oxide; inorganic violet pigments such as mango violet andcobalt violet; inorganic green pigments such as chromium oxide, chromiumhydroxide, and cobalt titanium oxide; inorganic blue pigments such asultramarine and prussian blue; pearl pigments such as titaniumoxide-coated mica, titanium oxide-coated bismuth oxychloride, titaniumoxide-coated talc, colored titanium oxide-coated mica, bismuthoxychloride, and fish scale guanine; metal powder pigments such asaluminum powder, copper powder, and gold; surface-treated inorganic andmetallic powder pigments; organic pigments such as zirconium lake,barium lake, and aluminum lake; surface-treated organic pigments;natural coloring agents and natural dyes such as astaxanthin,anthraquinones including alizarin, anthocyanidine, β-carotin, catenal,capsanthin, chalcone, carthamin, quercetin, crocin, chlorophyll,curcumin, cochineal, naphthoquinones including shikonin, bixin,flavones, betacyanin, henna, hemoglobin, lycopene, riboflavin, andrutin; oxidation dye intermediates and couplers such asp-phenylenediamine, toluene-2,5-diamine, o-, m-, and p-aminophenols,m-phenylenediamine, 5-amino-2-methyl phenol, resorcin, 1-naphthol,2,6-diaminopyridine, and the like, and salts thereof; autoxidizable dyessuch as indoline; and dihydroxyacetone.

Preferable examples of the antiphlogistics and the anti-inflammatoryagents include glycyrrhizic acid and derivatives thereof, glycyrrhetinicacid derivatives, salicylic acid derivatives, hinokitiol, guaiazulene,allantoin, indomethacin, ketoprofen, ibuprofen, diclofenac, loxoprofen,celecoxib, infliximab, etanercept, zinc oxide, hydrocortisone acetate,prednisone, diphenhydramine hydrochloride, and chlorpheniramine maleate;and plant extracts such as peach leaf extract and Artemisia princepsleaf extract.

Preferable examples of the anti-asthmatic agents, the drugs for chronicobstructive pulmonary disease, the antiallergic agents, and theimmunomodulators include aminophylline, theophyllines, steroids(fluticasone, beclomethasone, and the like), leukotriene antagonists,thromboxane inhibitors, Intal, β2-agonists (formoterol, salmeterol,albuterol, tulobuterol, clenbuterol, epinephrine, and the like),tiotropium, ipratropium, dextromethorphan, dimemorfan, bromhexine,tranilast, ketotifen, azelastine, cetirizine, chlorpheniramine,mequitazine, tacrolimus, cyclosporin, sirolimus, methotrexate, cytokinemodulators, interferon, omalizumab, and proteins and antibodies.

Preferable examples of the anti-infective agents and the antifungalagents include oseltamivir, zanamivir, and itraconazole. Other thanthese, known cosmetic ingredients, known pharmaceutical ingredients,known food ingredients, and the like such as ingredients described inThe Japanese Standards of Cosmetic Ingredients, Japanese CosmeticIngredients Codex, Japanese Cosmetic Labeling Name list issued by JapanCosmetic industry Association, INCI dictionary (The InternationalCosmetic Ingredient Dictionary and Handbook), Japanese Standards ofQuasi-drug Ingredients, Japanese Pharmacopoeia, Japanese PharmaceuticalExcipients, Japan's Specifications and Standards for Food Additives, andthe like and ingredients described in Japanese and foreign patentpublications and Patent Application Publications (including JapaneseTranslations of PCT International Applications and DomesticRe-Publications of PCT International Applications) categorized asInternational Patents Classification IPC of A61K7 and A61K8 can beincluded in a known combination and in a known formulation ratio or in aknown formulation amount.

[Method for Producing Hydrogel]

According to the present invention, a hydrogel can be produced by mixingthe disperse phase (A), that is, a disperse phase including the lipidpeptide-based gelator, the particular fatty acid salt, and water, andthe disperse phase (B) including the water-soluble acidic polymer.

More specifically, the method for producing a hydrogel according to thepresent invention includes:

a) preparing the disperse phase (A) including the lipid peptide-basedgelator, water, and the fatty acid salt,

b) adding the disperse phase (B) including the water-soluble acidicpolymer to the disperse phase (A), and

c) stirring the resulting mixture at room temperature and then leavingthe resulting mixture still standing to form a hydrogel.

The step a) of preparing the disperse phase (A) is preferably carriedout by mixing the lipid peptide-based gelator, water, and the fatty acidsalt at a high temperature with stirring and then leaving the resultingmixture to cool to reach room temperature.

[Hydrogel]

A hydrogel formed from the hydrogel-forming material and the dispersephases and a gel obtained by the method described above are also withinthe scope of the present invention.

EXAMPLES

The present invention will be described in more detail by examples andtest examples. The scope of the present invention, however, is notlimited to these examples.

Synthesis Example 1: Synthesis of Lipid Peptide (N-Palmitoyl-Gly-His)

A lipid peptide used in this example as a gelator was synthesized by amethod below.

14.2 g (91.6 mmol) of histidine, 30.0 g (91.6 mmol) ofN-palmitoyl-Gly-methyl, and 300 g of toluene were added to a 500-mLfour-necked flask, to which 35.3 g (183.2 mmol) of a 28% methanolsolution of sodium methoxide as a base was added, and the resultingsolution was heated in an oil bath to 60° C. and was stirred for 1 hour.Subsequently, the resulting solution that was removed from the oil bathwas left to cool to reach 25° C., was reprecipitated with 600 g ofacetone, and was filtered. The resulting solid was dissolved in a mixedsolution of 600 g of water and 750 g of methanol, to which 30.5 ml(183.2 mmol) of 6-N hydrochloric acid was added for neutralization toprecipitate a solid, which was filtered. The resulting solid was thendissolved in a mixed solution of 120 g of tetrahydrofuran and 30 g ofwater at 60° C., to which 150 g of ethyl acetate was added, and theresulting solution was cooled from 60° C. to 30° C. Subsequently, theprecipitated solid was filtrated. The resulting solid was dissolved in asolvent of 120 g of tetrahydrofuran and 60 g of acetonitrile and thenheated to 60° C. The resulting solution was stirred for 1 hour and thencooled, followed by filtration. The resulting solid was washed with 120g of water and filtrated, followed by drying under reduced pressure toobtain 26.9 g (yield: 65%) of a white crystal of a free form ofN-palmitoyl-Gly-His (hereinafter, also simply calledN-palmitoyl-Gly-His).

Example 1 to Example 14 and Comparative Example 1 to Comparative Example3: Preparation of Disperse Phase (A) (Premix) IncludingN-Palmitoyl-Gly-His and Evaluation of Dispersibility Thereof

The N-palmitoyl-Gly-His (called Pal-GH in tables) prepared in thesynthesis example, sodium palmitate (manufactured by Tokyo ChemicalIndustry Co., Ltd.) as an additive, and water were placed in a 300-mLbeaker at a proportion shown in the following tables, followed byheating to the liquid temperature of 80° C. for 20 minutes to 90 minuteswith stirring at 300 rpm. After the heating was terminated, theresulting solution was left to cool for 1 hour with stirring at 300 rpm.The amount of water lost by evaporation was added, followed by stirringat 300 rpm for another 1 minute. The resulting solution was left at roomtemperature overnight or longer to prepare a disperse phase (A). ALABORATORY HIGH POWER MIXER manufactured by As One Corporation was usedas a mixer for stirring.

Dispersibility in preparation of the disperse phase (A) was evaluated byvisual observation as, ◯ when the N-palmitoyl-Gly-His and the additivewere dispersed in water during the heating process and neitherseparation of water nor deposition of solid matter from the resultingdisperse phase (A) occurred, or as x when the N-palmitoyl-Gly-His and/orthe additive did not disperse in water during the heating process andsolid matter could be observed. The pH of the disperse phase (A) wasmeasured with a twin pH meter (manufactured by As One Corporation).

The results are shown in Table 1 to Table 4.

TABLE 1 Comparative Composition Examples Example (% by mass) 1 2 3 4 1Pal-GH 1.0 1.0 1.0 1.0 1.0 Sodium 0.30 0.61 1.23 1.85 — palmitate*¹Water Rest Rest Rest Rest Rest Total 100 100 100 100 100 Test resultsare as follows Dispersibility ◯ ◯ ◯ ◯ X in disperse phase (A) pH 10.310.3 9.7 10.3 — *¹manufactured by Tokyo Chemical Industry Co., Ltd.

TABLE 2 Composition Examples (% by mass) 5 6 7 8 9 Pal-GH 0.8 0.8 0.80.6 0.6 Sodium 0.25 0.49 1.48 0.18 0.37 palmitate*¹ Water Rest Rest RestRest Rest Total 100 100 100 100 100 Test results are as followsDispersibility ○ ○ ○ ○ ○ in disperse phase (A) pH 10.3 10.3 10.2 10.410.4 *¹manufactured by Tokyo Chemical industry Co., Ltd.

Table 3 Composition Examples (% by mass) 10 11 12 13 14 Pal-GH 0.6 0.50.5 0.4 0.4 Sodium 1.11 0.15 0.30 0.24 0.2 palmitate*¹ Water Rest RestRest Rest Rest Total 100 100 100 100 100 Test results are as followsDispersibility ○ ○ ○ ○ ○ in disperse phase (A) pH 10.3 10.3 10.4 10.410.3 *¹manufactured by Tokyo Chemical Industry Co., Ltd.

TABLE 4 Composition Comparative Examples (% by mass) 2 3 Pal-GH 0.4 —Sodium — 0.2 palmitate*¹ Water Rest Rest Total 100 100 Test results areas follows Dispersibility x x in disperse Phase (A) pH 7.8 10.5*¹manufactured by Tokyo Chemical Industry Co., Ltd.

Example 15 to Example 52 and Comparative Example 4 and ComparativeExample 5: Test for Neutralization and Gelation of Disperse Phase (A)(Premix) Including N-Palmitoyl-Gly-His

The disperse phase (A) including the N-palmitoyl-Gly-His obtained inExample 1 to Example 14 was placed in a 200-mL beaker at a proportionshown in the following tables, and, while stirring at 300 rpm, adisperse phase (B) (a polyacrylic acid (PAA) dispersion or a carbomerdispersion) shown below was added thereto, followed by stirring at 300rpm for 1 minute to prepare a hydrogel-forming material. A LABORATORYHIGH POWER MIXER manufactured by As One Corporation was used forstirring. The resulting mixture was left at room temperature for 1 hourand then a portion thereof was placed in a Mighty Vial (No. 3,manufactured by Maruemu Corporation).

Hydrogelation ability was evaluated as “gelled (◯)” when inversion ofthe vial did not make the solution flow down because the solution hadlost its fluidity or as “not gelled (x)” when the solution flowed down.Occurrence of syneresis in gel was also observed. In the case where themixture was gelled, the pH of the gel was measured with a twin pH meter(manufactured by As One Corporation), while in the case where themixture was not gelled, the pH of the liquid was measured in the samemanner. Final compositions after the hydrogelation test and the testresults are shown in the following tables. In the tables, the symbol “-”refers to the case where no test was performed.

TABLE 5 Composition Examples (% by mass) 15 16 17 18 Disperse Example 150 phase Example 2 50 Example 3 50 Example 4 50 0.4% PAA*² dispersion 5050 50 50 Water Total 100 100 100 100 Pal-GH 0.5 0.5 0.5 0.5 Sodiumpalmitate 0.15 0.305 0.615 0.925 PAA*² 0.2 0.2 0.2 0.2 Water Rest RestRest Rest Total 100 100 100 100 Test Results Evaluation of ○ ○ ○ ○hydrogelation ability pH 5.3 6.2 7.5 8.5 *²polyacrylic acid (molecularweight: 1,000,000) manufactured by Wako Pure Chemical Industries, Ltd.

TABLE 6 Composition (% by Examples mass) 19 20 21 22 23 Disperse Example2 50 50 50 phase Example 3 50 50 1.0% PAA*² 50 dispersion 0.4% PAA*² 50dispersion 0.2% PAA*² 50 dispersion 0.4% PAA*³ 50 dispersion 0.4% PAA*⁴50 dispersion Water Total 100 100 100 100 100 Pal-GH 0.5 0.5 0.5 0.5 0.5Sodium palmitate 0.305 0.615 0.615 0.305 0.305 PAA*² 0.1 0.5 0.2 PAA*³0.2 PAA*⁴ 0.2 Water Rest Rest Rest Rest Rest Total 100 100 100 100 100Test Results Evaluation of ◯ ◯ ◯ X X hydrogelation ability pH 8.8 5.37.1 6.0 6.1 *²polyacrylic acid (molecular weight: 1,000,000)manufactured by Wako Pure Chemical Industries, Ltd. *³polyacrylic acid(molecular weight: 25,000) manufactured by Wako Pure ChemicalIndustries, Ltd. *⁴polyacrylic acid (molecular weight: 5,000)manufactured by Wako Pure Chemical Industries, Ltd.

TABLE 7 Composition Examples (% by mass) 24 25 26 27 Disperse Example 225 phase Example 5 50 Example 6 50 Example 7 50 0.4% PAA*² dispersion 500.32% PAA*² dispersion  50 50 0.2% PAA*² dispersion 50 Water 25 25 Total100 100 100 100 Pal-GH 0.25 0.4 0.4 0.4 Sodium palmitate 0.152 0.1090.245 0.741 PAA*² 0.1 0.16 0.2 0.16 Water Rest Rest Rest Rest Total 100100 100 100 Test Results Evaluation of x ∘ ∘ x hydrogelation ability pH6.6 5.3 6.2 9.1 *²polyacrylic acid (molecular weight: 1,000,000)manufactured by Wako Pure Chemical Industries. Ltd.

TABLE 8 Composition (% by Examples mass) 28 29 30 31 32 Disperse Example6 25 12.5 phase Example 8 50 Example 9 50 Example 10 50 0.24% PAA*²dispersion 50 50 50 0.16% PAA*² dispersion 50 0.08% PAA*² dispersion 50Water 25 37.5 Total 100 100 100 100 100 Pal-GH 0.2 0.1 0.3 0.3 0.3Sodium palmitate 0.123 0.061 0.09 0.185 0.555 PAA*² 0.08 0.04 0.12 0.120.12 Water Rest Rest Rest Rest Rest Total 100 100 100 100 100 TestResults Evaluation of X X X ◯ X hydrogelation ability pH 6.4 6.8 5.5 6.45.3 *²polyacrylic acid (molecular weight: 1,000,000) manufactured byWako Pure Chemical Industries, Ltd.

TABLE 9 Composition Examples (% by mass) 31 34 35 Disperse Example 50 5050 phase 2 0.2% carbomer*⁵ 50 dispersion 0.1% carbomer*⁵ 50 dispersion0.05% carbomer*⁵  50 dispersion Water Total 100 100 100 Pal-GH 0.5 0.50.5 Sodium palmitate 0.305 0.305 0.305 Carbomer*⁵ 0.1 0.05 0.025 WaterRest Rest Rest Total 100 100 100 Test Results Evaluation of ∘ x xhydrogelation ability pH 7.5 9.5 9.8 *⁵Carbopol 940 manufactured by ITOInc.

TABLE 10 Composition Examples (% by mass) 36 37 38 39 Disperse Example11 50 phase Example 12 50 50 50 0.2% carbomer*⁵ 50 50 dispersion 0.1%carbomer*⁵ 50 dispersion 0.05% carbomer*⁵  50 dispersion Water Total 100100 100 100 Pal-GH 0.25 0.25 0.25 0.25 Sodium palmitate 0.075 0.15 0.150.15 Carbomer*⁵ 0.1 0.1 0.05 0.025 Water Rest Rest Rest Rest Total 100100 100 100 Test Results Evaluation of ∘ ∘ x x hydrogelation ability pH6.9 6.8 8.2 9.6 *⁵Carbopol 940 manufactured by ITO Inc.

TABLE 11 Composition Examples (% by mass) 40 41 42 43 Disperse Example13 50 50 phase Example 14 50 50 0.2% carbomer*⁵ 50 50 dispersion 0.1%carbomer*⁵ 50 50 dispersion Water Total 100 100 100 100 Pal-GH 0.2 0.20.2 0.2 Sodium palmitate 0.12 0.12 0.1 0.1 Carbomer*⁵ 0.1 0.05 0.1 0.05Water Rest Rest Rest Rest Total 100 100 100 100 Test Results Evaluationof ∘ x ∘ x hydrogelation ability pH 6.2 7.6 5.7 5.8 *⁵Carbopol 940manufactured by ITO inc.

TABLE 12 Composition (% by Examples mass) 44 45 46 47 48 DisperseExample 25 25 phase 14 Example 2 50 50 50 0.2% carbomer*⁵ 50 dispersion0.1% carbomer*⁵ 50 dispersion 0.2% carbomer*⁶ 50 dispersion 0.1%carbomer*⁶ 50 dispersion 0.05% carbomer*⁶ 50 dispersion Water 25 25Total 100 100 100 100 Pal-GH 0.1 0.1 0.5 0.5 0.5 Sodium palmitate 0.050.05 0.305 0.305 0.305 Carbomer*⁵ 0.1 0.05 Carbomer*⁶ 0.1 0.05 0.025Water Rest Rest Rest Rest Rest Total 100 100 100 100 100 Test ResultsEvaluation of X X ◯ X X hvdrogelation ability pH 6.3 6.6 7.9 9.3 10*⁵Carbopol 940 manufactured by ITO Inc. *⁶Hiviswako 105 manufactured byWako Pure Chemical Industries, Ltd.

TABLE 13 Composition Examples (% by mass) 49 50 51 52 Disperse Example12 50 50 50 phase Example 14 50 0.2% carbomer*⁶ 50 50 dispersion 0.1%carbomer*⁶ 50 dispersion 0.05% carbomer*⁶  50 dispersion Water Total 100100 100 100 Pal-GH 0.25 0.25 0.25 0.2 Sodium palmitate 0.15 0.15 0.150.1 Carbomer*5 0.1 0.05 0.025 0.1 Water Rest Rest Rest Rest Total 100100 100 100 Test Results Evaluation of ∘ x x ∘ hydrogelation ability pH6.4 8.0 9.5 6.0 *⁶Hiviswako 105 manufactured by Wako Pure ChemicalIndustries, Ltd.

TABLE 14 Composition Comparative Examples (% by mass) 4 5 DisperseComparative 50 phase Example 2 Comparative 50 Example 3 0.2% carbomer*⁵50 50 dispersion Water Total 100 100 Pal-GH 0.2 Sodium palmitate 0.1Carbomer*5 0.1 0.1 Water Rest Rest Total 100 100 Test Results Evaluationof x x hydrogelation ability pH 3.7 5.9 *⁵Carbopol 940 manufactured byITO Inc.

Example 53: Gel Spray Test on N-Palmitoyl-Gly-His Hydrogel

The hydrogel-forming material prepared in the examples was placed in aspray vial (Maruemu Corporation, 3L), followed by spraying twoconsecutive times toward the center of a glass plate (10 cm×7.5 cm) thatwas placed 5 cm away from the tip of the nozzle of the spray vial.Observation was performed until the dripping stopped, followed bymeasurement of the longer diameter and the shorter diameter of thesprayed mark on the glass and the length of the dripping. The results ofthe spray test are shown in the following tables. In the tables, thesymbol “-” refers to the case where no test was performed.

TABLE 15 Hydrogel-forming material Nos. (Example Nos.) Test Results 1516 17 18 19 20 21 22 Spray length (mm) 14 13 0 13 30 10 0 — Spray width(mm) 12 17 0 20 32 7 0 — Dripping (mm) 0 0 0 0 0 0 0 —

TABLE 16 Hydrogel-forming material Nos. (Example Nos.) Test Results 2324 25 26 27 28 29 30 31 Spray length (mm) — 25 25 10 26 40 34 24 22Spray width (mm) — 30 20 14 24 32 35 31 30 Dripping (mm) — 0 0 0 >20 0 010 0

TABLE 17 Hydrogel-forming material Nos. (Example Nos.) Test Results 3233 34 35 36 37 38 Spray length (mm) 28 0 20 10 27 12 35 Spray width (mm)30 0 25 7 30 11 30 Dripping (mm) >20 0 0 0 0 0 0

TABLE 18 Hydrogel-forming material Nos. (Example Nos.) Test Results 3940 41 42 43 44 45 Spray length (mm) 20 20 50 37 40 28 30 Spray width(mm) 23 23 50 39 35 27 32 Dripping (mm) >15 0 0 0 0 0 3

TABLE 19 Hydrogel-forming material Nos. (Example Nos.) Test Results 4647 48 49 50 51 52 Spray length (mm) 21 25 24 14 41 38 28 Spray width(mm) 21 23 25 19 35 34 21 Dripping (mm) 0 0 >15 0 0 5 0

Example 54: Test to Evaluate Re-Forming Ability of N-Palmitoyl-Gly-HisHydrogel

In a Mighty Vial (No. 3, manufactured by Maruemu Corporation), 4 g ofthe hydrogel-forming material prepared in the examples was placed,followed by stirring with a vortex mixer (Scientific Industries, Inc.)for 1 minute. Then, the vial was left still standing at room temperatureovernight or longer. Evaluation was conducted as “not converted into asol (Δ)” when no solation was confirmed after mixing with the vortexmixer, as “re-formed (◯)” when the solution lost its fluidity afterbeing converted into a sol and left still standing, and inversion of thevial did not make the solution flow down, or as “not re-formed (x)” whenthe solution flowed down. The symbol “-” refers to the case where notest was performed.

TABLE 20 Hydrogel-forming material Nos. (Example Nos.) Test Result 15 1617 18 19 20 21 22 Hydrogel re-forming ◯ ◯ Δ X ◯ Δ Δ — ability

TABLE 21 Hydrogel-forming material Nos. (Example Nos.) Test Result 23 2425 26 27 28 29 30 31 Hydrogel re-forming — — X ◯ — — — — ◯ ability

TABLE 22 Hydrogel-forming material Nos. (Example Nos.) Test Result 32 3334 35 36 37 38 Hydrogel re-forming — Δ — — ◯ Δ — ability

TABLE 23 Hydrogel-forming material Nos. (Example Nos.) Test Result 39 4041 42 43 44 45 Hydrogel re-forming — Δ — Δ — — — ability

TABLE 24 Hydrogel-forming material Nos. (Example Nos.) Test Result 46 4748 49 50 51 52 Hydrogel re-forming Δ — — Δ — — — ability

Example 55 to Example 73: Test for Neutralization and Gelation ofN-Palmitoyl-Gly-His <Preparation of Phase A (Disperse Phase IncludingPal-GH)>

The N-palmitoyl-Gly-His prepared in the synthesis example, a fatty acid,a 1-N aqueous sodium hydroxide solution, purified water, and otheradditives were placed in a 300-mL beaker at a proportion shown in thefollowing tables, followed by heating to a the liquid temperature of 80°C. for 30 minutes with stirring at 300 rpm. The “Rest” in the row“Purified water” refers to the value obtained by subtracting the amountof the components in the phase A and the phase B other than purifiedwater from the sum (100% by mass) of the components in the phase A andthe phase B. Then, heating was terminated and the resulting mixture wasleft to cool for 1 hour with stirring at 300 rpm. The amount of waterlost by evaporation was added, followed by stirring at 300 rpm foranother 1 minute. The resulting mixture was left at room temperatureovernight or longer to prepare a disperse phase including PalGH to serveas a phase A. In Comparative Example 6 to Comparative Example 9, thephases A did not include Pal-GH.

In these examples, A LABORATORY HIGH POWER MIXER manufactured by As OneCorporation was used for stirring.

<Preparation of Phase B (Disperse Phase Including Water-Soluble AcidicPolymer)>

A water-soluble acidic polymer (a carboxyvinyl polymer, an acrylicacid-alkyl methacrylate copolymer), purified water, and other additiveswere placed in a 200-mL beaker at a proportion shown in the followingtables, followed by stirring at 300 rpm at room temperature (about 25°C.) to adequately disperse the components to prepare a disperse phaseincluding a water-soluble acidic polymer to serve as a phase B. InComparative Example 10 and Comparative Example 11, citric acid or lacticacid was used instead of the acidic polymer.

<Preparation of Hydrogel-Forming Material and Hydrogel>

The phase B (disperse phase including a water-soluble acidic polymer)was added to the phase A (disperse phase including PalGH) obtained asdescribed above at room temperature (about 25° C.) with stirring at 300rpm, followed by stirring for about 10 minutes to prepare ahydrogel-forming material. A portion of the resulting mixture was placedin a Mighty Vial (No. 3, manufactured by Maruemu Corporation), which wasthen left still standing at room temperature for 1 hour. Hydrogelationability was evaluated as “hard gel formed (⊙)” when inversion of thevial did not make the solution flow down because the solution had lostits fluidity and the gel formed was hard enough not to disintegrate dueto vibration applied thereto, as “gelled (◯)” when the gel formed becamefluid due to vibration applied thereto, or as “not gelled (x)” when theresulting solution flowed down. A twin pH meter (manufactured by As OneCorporation) was used to measure the pH of the gel in the case where themixture was gelled or the pH of the sol in the case where the mixturewas not gelled. Final compositions after the hydrogelation test and thetest results are shown in the following tables.

TABLE 25 Composition Examples (% by mass) 55 56 57 58 A Pal-GH 0.5 0.50.2 0.2 palmitic 0.25 0.25 0.1 0.1 acid*⁷ 1 mol/L 1.02 1.02 0.41 0.41aqueous sodium hydroxide solution*⁸ purified Rest Rest Rest Rest water Bcarboxyvinyl 0.2 0.1 0.2 0.1 polymer*⁹ purified 49.8 49.9 49.8 49.9water Total 100 100 100 100 Evaluation of ⊚ ⊚ ⊚ ◯ hydrogelation abilitypH 6.5 8.5 5.3 6.5 *⁷manuflictured by Kao Corporation. Lunac P-95*⁸manufactured by Junsei Chemical Co., Ltd. *⁹manufactured by ITO Inc.Carbopol 940

TABLE 26 Composition Comparative Examples (% by mass) 6 7 8 9 A Pal-GH 00 0 0 palmitic 0.25 0.25 0.1 0.1 acid*⁷ 1 mol/L 1.02 1.02 0.41 0.41aqueous sodium hydroxide solution*⁸ purified Rest Rest Rest Rest water Bcarboxyvinyl 0.2 0.1 0.2 0.1 polymer*⁹ purified 49.8 49.9 49.8 49.9water Total 100 100 100 100 Evaluation of x x x x hydrogelation abilitypH 6.8 8.2 5.5 6.5 *⁷manufactured by Kao Corporation, Lunac P-95*⁸manufactured by Junsei Chemical Co., Ltd. *⁹manufactured by ITO Inc.Carbopol 940

Table 27 Composition Examples (% by mass) 59 60 61 62 A Pal-GH 0.5 0.50.2 0.2 stearic 0.25 0.25 0.1 0.1 acid*¹⁰ oleic acid*¹¹ — — — — 1 mol/L0.92 0.92 0.37 0.37 aqueous sodium hydroxide solution*⁸ purified RestRest Rest Rest water B carboxyvinyl 0.2 0.1 0.2 0.1 polymer*⁹ purified49.8 49.9 49.8 49.9 water Total 100 100 100 100 Evaluation of ⊚ ⊚ ⊚ ◯hydrogelation ability pH 6.5 8.2 5.3 6.3 *⁸manufactured by JunseiChemical Co., Ltd. *⁹manufactured by ITO Inc. Carbopol 940*¹⁰manufactured by Kao Corporation. Lunac S-98 *¹¹manufactured by KaoCorporation. Lunac O-LL-V

TABLE 28 Composition Examples (% by mass 63 64 65 66 A Pal-GH 0.5 0.50.2 0.2 stearic — — — — acid*¹⁰ oleic acid*¹¹ 0.25 0.25 0.1 0.1 1 mol/L0.92 0.92 0.37 0.37 aqueous sodium hydroxide solution*⁸ purified RestRest Rest Rest water B carboxyvinyl 0.1 0.1 0.1 0.1 polymer*⁹ purified49.8 49.9 49.8 49.9 water Total 100 100 100 100 Evaluation of ⊚ ⊚ ⊚ ◯hydrogelation ability pH 6.5 7.8 5.6 5.7 *⁸manufactured by JunseiChemical Co., Ltd. *⁹manufactured by ITO Inc. Carbopol 940*¹⁰manufactured by Kao Corporation, Lunac S 98 *¹¹manufactured by KaoCorporation. Lunac O-LL-V

TABLE 29 Composition (% by Examples mass) 67 68 69 70 71 A Pal-GH 0.50.5 0.5 0.5 0.5 palmitic 0.25 0.25 0.25 0.25 0.25 acid*⁷ 1 mol/L 1.021.02 1.02 1.02 1.02 aqueous sodium hydroxide solution*⁸ 1,3-butylene 10glycol*¹² glycerin*¹³ 10 purified Rest Rest Rest Rest Rest water Bcarboxyvinyl 0.2 0.2 0.2 0.2 0.2 polymer*⁹ 1,3-butylene 10 glycol*¹²Glycerin*¹³ 10 purified 49.8 49.8 49.8 39.8 39.8 water Total 100 100 100100 100 Evaluation of ⊙ ⊙ ⊙ ⊙ ⊙ hydrogelation ability pH 6.5 6.6 6.7 6.86.7 *⁷manufactured by Kao Corporation. Lunac P-95 *⁸manufactured byJunsei Chemical Co., Ltd. *⁹manufactured by ITO Inc. Carbopol 940*¹²manufactured by ITO Inc. *¹³manufactured by ITO Inc.

TABLE 30 Composition Examples Comparative Examples (% by mass 72 73 1011 A Pal-GH 0.5 0.5 0.5 0.5 palmitic acid*⁷ 0.25 0.25 0.25 0.25 1 mol/L1.02 1.02 1.02 1.02 aqueous sodium hydroxide solution*⁸ purified RestRest Rest Rest water B carboxyvinyl 0.2 polymer*₉ acrylic 0.2 acid-alkylmethacrylate copolymer*¹⁴ citric acid*¹⁵ 0.2 lactic acid*¹⁶ 0.2 purified49.8 49.8 49.8 49.8 water Total 100 100 100 100 Evaluation of ⊚ ⊚ X Xhydrogelation ability pH 6.5 6.5 4.2 4.3 *⁷manufactured by KaoCorporation. Lunac P-95 *⁸manufactured by Junsei Chemical Co., Ltd.*⁹manufactured by ITO Inc. Carbopol 940 *¹⁴manufactured by NikkoChemicals Co., Ltd. PEMULEN TR-1 *¹⁵manufactured by Wako Pure ChemicalIndustries, Ltd. *¹⁶manufactured by Wako Pure Chemical Industries, Ltd.

1. A premix for preparation of a hydrogel for use in a cosmetic or aquasi drug, the premix comprising: a lipid peptide-based gelatorconsisting of at least one of a compound of Formula (1) or apharmaceutically usable salt thereof; water; and a fatty acid salt:

(where R¹ is a C₉₋₂₃ aliphatic group, R² is a hydrogen atom or a C₁₋₄alkyl group that optionally has a C₁₋₂ branched chain, R³ is a—(CH₂)_(n)—X group, n is a number of 1 to 4, X is an amino group, aguanidino group, a —CONH₂ group, a 5-membered ring optionally containing1 to 3 nitrogen atom(s), a 6-membered ring optionally containing 1 to 3nitrogen atom(s), or a condensed heterocycle that contains a 5-memberedring and a 6-membered ring optionally containing 1 to 3 nitrogenatom(s)).